U.S. patent application number 11/966585 was filed with the patent office on 2008-08-07 for bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as axl inhibitors.
This patent application is currently assigned to RIGEL PHARMACEUTICALS, INC.. Invention is credited to Pingyu Ding, Dane Goff, Thilo J. Heckrodt, Sacha Holland, Joane Litvak, Rajinder Singh, Jiaxin Yu, Jing Zhang.
Application Number | 20080188454 11/966585 |
Document ID | / |
Family ID | 39259637 |
Filed Date | 2008-08-07 |
United States Patent
Application |
20080188454 |
Kind Code |
A1 |
Goff; Dane ; et al. |
August 7, 2008 |
BICYCLIC ARYL AND BICYCLIC HETEROARYL SUBSTITUTED TRIAZOLES USEFUL
AS AXL INHIBITORS
Abstract
Bicyclic aryl substituted triazoles or heteroaryl substituted
triazoles and pharmaceutical compositions containing the compounds
are disclosed as being useful in inhibiting the activity of the
receptor protein tyrosine kinase Axl. Methods of using the
compounds in treating diseases or conditions associated with Axl
activity are also disclosed.
Inventors: |
Goff; Dane; (Redwood City,
CA) ; Zhang; Jing; (Foster City, CA) ; Singh;
Rajinder; (Belmont, CA) ; Holland; Sacha; (San
Francisco, CA) ; Yu; Jiaxin; (San Carlos, CA)
; Ding; Pingyu; (Foster City, CA) ; Heckrodt;
Thilo J.; (San Francisco, CA) ; Litvak; Joane;
(Oakland, CA) |
Correspondence
Address: |
SEED INTELLECTUAL PROPERTY LAW GROUP PLLC
701 FIFTH AVENUE, SUITE 5400
SEATTLE
WA
98104-7092
US
|
Assignee: |
RIGEL PHARMACEUTICALS, INC.
South San Francisco
CA
|
Family ID: |
39259637 |
Appl. No.: |
11/966585 |
Filed: |
December 28, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60975346 |
Sep 26, 2007 |
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60882769 |
Dec 29, 2006 |
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Current U.S.
Class: |
514/210.21 ;
514/217.06; 514/252.16; 540/476; 540/600; 544/253 |
Current CPC
Class: |
A61P 35/02 20180101;
A61P 17/06 20180101; A61P 35/00 20180101; A61K 31/395 20130101;
A61P 13/12 20180101; C07D 401/14 20130101; C07D 495/04 20130101;
C07D 417/14 20130101; A61P 19/10 20180101; C07D 403/14 20130101;
C07D 403/04 20130101; A61K 31/519 20130101; A61P 9/00 20180101;
A61P 29/00 20180101; A61P 19/00 20180101 |
Class at
Publication: |
514/210.21 ;
544/253; 540/600; 540/476; 514/252.16; 514/217.06 |
International
Class: |
A61K 31/496 20060101
A61K031/496; C07D 239/70 20060101 C07D239/70; A61K 31/55 20060101
A61K031/55; A61P 35/00 20060101 A61P035/00; A61P 35/02 20060101
A61P035/02; A61K 31/397 20060101 A61K031/397; C07D 403/14 20060101
C07D403/14 |
Claims
1. A compound of formula (I): ##STR00192## wherein: R.sup.1,
R.sup.4 and R.sup.5 are each independently selected from group
consisting of hydrogen, alkyl, aryl, aralkyl, --C(O)R.sup.9 and
--C(O)N(R.sup.6)R.sup.7; R.sup.2 and R.sup.3 are each independently
a bicyclic aryl or a bicyclic heteroaryl of formula (II):
##STR00193## where: A is an alkylene chain containing six to ten
carbons, an alkenylene chain containing six to ten carbons, or an
alkynylene chain containing six to ten carbons, where one or two
carbons of the alkylene, alkenylene or alkynylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain, the
alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
or R.sup.2 is selected from the group consisting of a bicyclic aryl
and a bicyclic heteroaryl of formula (II), as defined above, and
R.sup.3 is selected from the group consisting of aryl and
heteroaryl wherein the aryl and heteroaryl are each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.20)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9; as an
isolated stereoisomer or a mixture thereof, or a pharmaceutically
acceptable salt thereof.
2. The compound of claim 1, which is a compound of formula (Ia):
##STR00194## wherein: R.sup.1, R.sup.4 and R.sup.5 are each
independently selected from group consisting of hydrogen, alkyl,
aryl, aralkyl, --C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7; R.sup.2
and R.sup.3 are each independently a bicyclic aryl or a bicyclic
heteroaryl of formula (II): ##STR00195## where: A is an alkylene
chain containing six to ten carbons, an alkenylene chain containing
six to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
or R.sup.2 is selected from the group consisting of a bicyclic aryl
and a bicyclic heteroaryl of formula (II), as defined above, and
R.sup.3 is selected from the group consisting of aryl and
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9; as an
isolated stereoisomer or a mixture thereof, or a pharmaceutically
acceptable salt thereof.
3. The compound of claim 2 wherein: R.sup.1, R.sup.4 and R.sup.5
are each independently selected from group consisting of hydrogen,
alkyl, aryl, aralkyl, --C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7;
R.sup.2 is a bicyclic aryl or a bicyclic heteroaryl of formula
(II): ##STR00196## where: A is an alkylene chain containing six to
ten carbons, an alkenylene chain containing six to ten carbons, or
an alkynylene chain containing six to ten carbons, where one or two
carbons of the alkylene, alkenylene or alkynylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain, the
alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; R.sup.3 is selected from the
group consisting of aryl and heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.20)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9.
4. The compound of claim 3 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl of formula (II):
##STR00197## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is a monocyclic aryl or a monocyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--OC(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
5. The compound of claim 3 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00198## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; R.sup.3 is a monocyclic aryl
or a monocyclic heteroaryl, each optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
6. The compound of claim 5 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00199## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached R.sup.3 is a monocyclic aryl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--OC(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
7. The compound of claim 5 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00200## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is monocyclic heteroaryl optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
8. The compound of claim 6 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00201## where: A is an alkylene chain containing six
carbons, where one carbon of the alkylene chain is replaced by
--NR.sup.9-- and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is monocyclic heteroaryl selected from
the group consisting of furanyl, pyranyl, pyridinyl, pyrimidinyl
and pyridazinyl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl, aryl,
and aralkyl and each R.sup.15 is independently a direct bond or a
straight or branched alkylene chain; each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, haloalkenyl, hydroxyalkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2; each R.sup.8 is independently
selected from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, and optionally substituted heteroarylalkyl; each
R.sup.10 is independently selected from the group consisting of a
direct bond and an optionally substituted straight or branched
alkylene chain; and each R.sup.11 is an optionally substituted
straight or branched alkylene chain.
9. The compound of claim 8 which is
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-9-yl)-1-(5-(tr-
ifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine.
10. The compound of claim 3 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00202## where: A is an alkylene chain containing six
carbons, where at least one carbon of the alkylene chain is
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is a bicyclic heteroaryl selected from
the group consisting of benzothiazolyl, benzofuranyl, indolyl,
benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
quinoxalinyl, imidazopyrimidinyl, pyrrolopyrimidinyl,
furopyrimidinyl, thienopyrimidinyl, thienopyridazinyl,
furopyridazinyl, pyrrolopyridazinyl, imidazopyridazinyl,
thienopyrazinyl, furopyrazinyl, pyrrolopyrazinyl and
imidazopyridinyl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, R.sup.15--N(R.sup.14).sub.2,
R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
11. The compound of claim 10 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00203## where: A is an alkylene chain containing six
carbons, where at least one carbon of the alkylene chain is
replaced by --NR.sup.9-- or --O-- and where each carbon in the
alkylene chain is independently optionally substituted by one or
two substituents selected from the group consisting of oxo, thioxo,
cyano, nitro, halo, haloalkyl, alkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is a bicyclic heteroaryl selected from
the group consisting of thienopyrimidinyl, quinazolinyl and
benzothiazolyl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, oxo, thioxo, cyano, nitro, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
12. The compound of claim 11 selected from the group consisting of:
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-(6-flu-
oroquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenz-
o[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenz-
o[d]azocin-9-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N'-(2,3,4,5-tetrahydrobe-
nzo[b][1,4]dioxocin-8-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydro-benzo[d]azocin-8-yl)-1-(6,7--
dimethoxyquinazolin-4-yl)-1H-[1,2,4]triazole-3,5-diamine;
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(3-cyclopentyl-1-
,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azoci-
n-8-yl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-
-3,5-diamine;
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azoci-
n-8-yl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-(7-met-
hylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azoci-
n-8-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diam-
ine;
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(2-chloro--
7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(7-methylthien-
o[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine; and
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(6,7-dimethoxy-
quinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine.
13. The compound of claim 3 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl of formula (II):
##STR00204## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is a bicyclic aryl or a bicyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
14. The compound of claim 13 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl of formula (II):
##STR00205## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is a bicyclic heteroaryl selected from
the group consisting of benzothiazolyl, benzofuranyl, indolyl,
benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
quinoxalinyl, imidazopyrimidinyl, pyrrolopyrimidinyl,
furopyrimidinyl, thienopyrimidinyl, thienopyridazinyl,
furopyridazinyl, pyrrolopyridazinyl, imidazopyridazinyl,
thienopyrazinyl, furopyrazinyl, pyrrolopyrazinyl and
imidazopyridinyl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, oxo, thioxo, cyano, nitro, R.sup.15--OR.sup.14--,
R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
15. The compound of claim 14 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl of formula (II):
##STR00206## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is thienopyrimidinyl optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, oxo, thioxo, cyano,
nitro, --R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
16. The compound of claim 15 which is
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(9-(pyrrolidin-1-
-yl)-5,6,7,8,9,10-hexahydrobenzo[8]annulen-2-yl)-1H-1,2,4-triazole-3,5-dia-
mine.
17. The compound of claim 3 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00207## where: A is an alkylene chain containing six
carbons where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; R.sup.3 is a bicyclic
heteroaryl optionally substituted by one or more substitutents
selected from the group consisting of alkyl, alkenyl, halo,
haloalkyl, oxo, thioxo, cyano, nitro, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.14, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
18. The compound of claim 17 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00208## where: A is an alkylene chain containing six
carbons where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; R.sup.3 is a bicyclic
heteroaryl selected from the group consisting of benzothiazolyl,
benzofuranyl, indolyl, benzimidazolyl, indazolyl, quinolinyl,
isoquinolinyl, quinazolinyl, quinoxalinyl, imidazopyrimidinyl,
pyrrolopyrimidinyl, furopyrimidinyl, thienopyrimidinyl,
thienopyridazinyl, furopyridazinyl, pyrrolopyridazinyl,
imidazopyridazinyl, thienopyrazinyl, furopyrazinyl,
pyrrolopyrazinyl and imidazopyridinyl, each optionally substituted
by one or more substitutents selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, oxo, thioxo, cyano, nitro,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
19. The compound of claim 18 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00209## where: A is an alkylene chain containing six
carbons where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; R.sup.3 is thienopyrimidinyl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, alkenyl, halo, haloalkyl, oxo,
thioxo, cyano, nitro, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2; each R.sup.8 is independently
selected from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
20. The compound of claim 19 selected from the group consisting of:
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-oxo-5,6,8,9,1-
0-pentahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrrolidin-1-
-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-
-diamine;
1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrrolidin-1-
-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-
-diamine;
N.sup.3-(7-(cyclohexylamino)-5,6,7,8,9,10-hexahydrocycloocta[b]p-
yridin-3-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-
-diamine;
N.sup.3-(7-(4-methylpiperazin-1-yl)-5,6,7,8,9,10-hexahydrocycloo-
cta[b]pyridin-3-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triaz-
ole-3,5-diamine.
21. The compound of claim 3 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl or a bicyclic
heteroaryl of formula (II): ##STR00210## where: A is an alkylene
chain containing six carbons, where one or two carbons of the
alkylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain
is independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; R.sup.3 is a tricyclic aryl
or a tricyclic heteroaryl, each optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
22. The compound of claim 21 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl of formula (II):
##STR00211## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; R.sup.3 is a tricyclic aryl or a tricyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, halo,
haloalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
23. The compound of claim 21 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula
(II): ##STR00212## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.2 is attached; R.sup.3 is a
tricyclic aryl or a tricyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, halo, haloalkyl, oxo, thioxo, cyano, nitro,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
24. The compound of claim 2 wherein: R.sup.1, R.sup.4 and R.sup.5
are each independently selected from group consisting of hydrogen,
alkyl, aryl, aralkyl, --C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7;
R.sup.2 is an aryl or a heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--C(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic aryl or a bicyclic
heteroaryl of formula (II): ##STR00213## where: A is an alkylene
chain containing six to ten carbons, an alkenylene chain containing
six to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10, --R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.3 is attached; each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9.
25. The compound of claim 24 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a monocyclic aryl or a monocyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--OC(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic aryl of formula (II):
##STR00214## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.3 is attached; each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
26. The compound of claim 24 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a monocyclic aryl or a monocyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00215## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
27. The compound of claim 26 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a monocyclic aryl optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00216## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
28. The compound of claim 27 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is phenyl optionally substituted by one
or more substitutents selected from the group consisting of alkyl,
alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00217## where: A is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1 is .dbd.N--, B.sup.2 is the carbon directly bonded to the
nitrogen to which R.sup.3 is attached, B.sup.3 is .dbd.N-- and
B.sup.4 is .dbd.C(R.sup.8)--; each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
29. The compound of claim 28 selected from the group consisting of:
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
(R)--N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
(S)--N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-chloro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-((4-methy-
lpiperazin-1-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-fluoro-4-(4-morpholinopiperidin-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(4-(4-(4-fluorophenyl)piperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexa-
hydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
ethyl
4-(4-(5-amino-1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2-
,4-triazol-3-ylamino)-2-fluorophenyl)piperazine-1-carboxylate;
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(2-methyl-
-2-(pyrrolidin-1-yl)propoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
and
N.sup.3-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-1-(5,6,7,8,-
9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine.
30. The compound of claim 26 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is phenyl optionally substituted by one
or more substitutents selected from the group consisting of alkyl,
alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00218## where: A is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1 is .dbd.C(R.sup.8)--, B.sup.2 is the carbon directly bonded
to the nitrogen to which R.sup.3 is attached, B.sup.3 and B.sup.4
are both .dbd.N--; each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
31. The compound of claim 30 selected from the group consisting of:
N.sup.3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
and
1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-N.sup.3-(4-(2-(p-
yrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.
32. The compound of claim 27 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is phenyl optionally substituted by one
or more substitutents selected from the group consisting of alkyl,
alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14, --R.sup.15--
OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00219## where: A is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1 is the carbon directly bonded to the nitrogen to which
R.sup.3 is attached, B.sup.2 and B.sup.4 are both .dbd.N-- and
B.sup.3 is .dbd.C(R.sup.8)--; each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
33. The compound of claim 32 selected from the group consisting of:
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine; and
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
and
N.sup.3-(3-fluoro-4-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)-1-(5,6,-
7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamin-
e.
34. The compound of claim 27 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is phenyl optionally substituted by one
or more substitutents selected from the group consisting of alkyl,
alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00220## where: A is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1 is .dbd.N--, B.sup.2 is the carbon directly bonded to the
nitrogen to which R.sup.3 is attached, and B.sup.3 and B.sup.4 are
both .dbd.C(R.sup.8)--; each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
35. The compound of claim 34 selected from the group consisting of:
1-(5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(4-methylpi-
perazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(2-(pyrroli-
din-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(4-pheny-
l-5,6,7,8,9,10-hexahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-d-
iamine;
N.sup.3-(4-(4-methylpiperazin-1-yl)phenyl)-1-(4-phenyl-5,6,7,8,9,1-
0-Hexahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
and
N.sup.3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(4-phenyl-5,6,7,8,9,10-he-
xahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine.
36. The compound of claim 26 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a monocyclic heteroaryl optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00221## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
37. The compound of claim 36 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is pyridinyl optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00222## where: A is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1 is the carbon directly bonded to the nitrogen to which
R.sup.3 is attached, B.sup.2 and B.sup.4 are both .dbd.N-- and
B.sup.3 is .dbd.C(R.sup.8)--; each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
38. The compound of claim 37 selected from the group consisting of:
N.sup.3-(6-(4-(azepan-1-yl)piperidin-1-yl)pyridin-3-yl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
and
N.sup.3-(6-(4-((pyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-1-(5,-
6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diam-
ine.
39. The compound of claim 24 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl or a bicyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--C(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic aryl or a bicyclic
heteroaryl of formula (II): ##STR00223## where: A is an alkylene
chain containing six carbons, where one or two carbons of the
alkylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain
is independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.3 is attached; each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
40. The compound of claim 39 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl or a bicyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic aryl of formula (II):
##STR00224## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.3 is attached; each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
41. The compound of claim 39 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl or a bicyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00225## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
42. The compound of claim 41 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl selected from
the group consisting of benzothiazolyl, benzofuranyl, indolyl,
benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
quinoxalinyl, imidazopyrimidinyl, pyrrolopyrimidinyl,
furopyrimidinyl, thienopyrimidinyl, thienopyridazinyl,
furopyridazinyl, pyrrolopyridazinyl, imidazopyridazinyl,
thienopyrazinyl, furopyrazinyl, pyrrolopyrazinyl and
imidazopyridinyl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, oxo, thioxo, cyano, nitro,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00226## where: A is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1 is .dbd.N--, B.sup.2 is the carbon directly bonded to the
nitrogen to which R.sup.3 is attached, B.sup.3 is .dbd.N-- and
B.sup.4 is .dbd.C(R.sup.8)--; each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
43. The compound of claim 42 which is
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(2-methyl-1,-
2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine.
44. The compound of claim 24 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a tricyclic aryl or a tricyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic aryl or a bicyclic
heteroaryl of formula (II): ##STR00227## where: A is an alkylene
chain containing six carbons, where one or two carbons of the
alkylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain
is independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.3 is attached; each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
45. The compound of claim 44 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a tricyclic aryl or a tricyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic aryl of formula (II):
##STR00228## where: A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.3 is attached; each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
46. The compound of claim 44 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a tricyclic aryl or a tricyclic
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; R.sup.3 is a bicyclic heteroaryl of formula
(II): ##STR00229## where: A is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
47. The compound of claim 2 wherein: R.sup.1, R.sup.4 and R.sup.5
are each independently selected from group consisting of hydrogen,
alkyl, aryl, aralkyl, --C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7;
R.sup.2 and R.sup.3 are each independently a bicyclic aryl or a
bicyclic heteroaryl of formula (II): ##STR00230## where: A is an
alkylene chain containing six to ten carbons, an alkenylene chain
containing six to ten carbons, or an alkynylene chain containing
six to ten carbons, where one or two carbons of the alkylene,
alkenylene or alkynylene chain is optionally replaced by
--NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p is 0, 1 or
2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where each carbon
in the alkylene chain, the alkenylene chain or the alkynylene chain
is independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
each R.sup.6 and R.sup.7 is independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aralkenyl, optionally substituted aralkynyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.11--OR.sup.9,
--R.sup.11--CN, --R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9.
48. The compound of claim 47 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 and R.sup.3 are each a bicyclic aryl of
formula (II): ##STR00231## where: A is an alkylene chain containing
six carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
each R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.11--OR.sup.9,
--R.sup.11--CN, --R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
49. The compound of claim 47 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 and R.sup.3 are each a bicyclic
heteroaryl of formula (II): ##STR00232## where: A is an alkylene
chain containing six carbons, where one or two carbons of the
alkylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain
is independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which its corresponding R.sup.2 or R.sup.3 is
attached; each R.sup.6 and R.sup.7 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.11--OR.sup.9,
--R.sup.11--CN, --R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
50. The compound of claim 47 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic aryl of formula (II)
having the following formula (IIa): ##STR00233## where: Aa is an
alkylene chain containing six carbons, where each carbon in the
alkylene chain is independently optionally substituted by one or
two substituents selected from the group consisting of oxo, thioxo,
cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1a, B.sup.2a,
B.sup.3a and B.sup.4a is a carbon directly bonded to the nitrogen
to which R.sup.2 is attached; R.sup.3 is a bicyclic heteroaryl of
formula (II) having the following formula (IIb): ##STR00234##
where: Ab is an alkylene chain containing six carbons, where each
carbon of the alkylene chain may be replaced by --NR.sup.9--,
.dbd.N--, --O--, --S(O).sub.p-- (where p is 0, 1 or 2) or
--P(O).sub.p-- (where p is 0, 1 or 2) and where each carbon in the
alkylene chain is independently optionally substituted by one or
two substituents selected from the group consisting of oxo, thioxo,
cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl,
optionally substituted heteroaryl, optionally substituted
heterocyclyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.11--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b is .dbd.N-- and one of
B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b is a carbon directly
bonded to the nitrogen to which R.sup.3 is attached; each R.sup.6
and R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
51. The compound of claim 47 wherein: R.sup.1, R.sup.4 and R.sup.5
are each hydrogen; R.sup.2 is a bicyclic heteroaryl of formula (II)
having the following formula (IIa): ##STR00235## where: Aa is an
alkylene chain containing six carbons, where one or two carbons of
the alkylene chain is optionally replaced by --NR.sup.9--,
.dbd.N--, --O--, --S(O).sub.p-- (where p is 0, 1 or 2) or
--P(O).sub.p-- (where p is 0, 1 or 2) and where each carbon in the
alkylene chain is independently optionally substituted by one or
two substituents selected from the group consisting of oxo, thioxo,
cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a is .dbd.N-- and that one
of B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a is a carbon directly
bonded to the nitrogen to which R.sup.2 is attached; R.sup.3 is a
bicyclic aryl of formula (II) having the following formula (IIb):
##STR00236## where: Ab is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1b, B.sup.2b,
B.sup.3b and B.sup.4b is a carbon directly bonded to the nitrogen
to which R.sup.3 is attached; each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.11 is an optionally substituted straight or branched
alkylene chain.
52. The compound of claim 1, which is a compound of formula (Ib):
##STR00237## wherein: R.sup.1, R.sup.4 and R.sup.5 are each
independently selected from group consisting of hydrogen, alkyl,
aryl, aralkyl, --C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7; R.sup.2
and R.sup.3 are each independently a bicyclic aryl or a bicyclic
heteroaryl of formula (II): ##STR00238## where: A is an alkylene
chain containing six to ten carbons, an alkenylene chain containing
six to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
or R.sup.2 is selected from the group consisting of a bicyclic aryl
and a bicyclic heteroaryl of formula (II), as defined above, and
R.sup.3 is selected from the group consisting of aryl and
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
R.sup.15--OC(O)--R.sup.14, R.sup.15--N(R.sup.14).sub.2,
R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.20)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9; as an
isolated stereoisomer or a mixture thereof, or a pharmaceutically
acceptable salt thereof.
53. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound of formula (I): ##STR00239##
wherein: R.sup.1, R.sup.4 and R.sup.5 are each independently
selected from group consisting of hydrogen, alkyl, aryl, aralkyl,
--C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7; R.sup.2 and R.sup.3 are
each independently a bicyclic aryl or a bicyclic heteroaryl of
formula (II): ##STR00240## where: A is an alkylene chain containing
six to ten carbons, an alkenylene chain containing six to ten
carbons, or an alkynylene chain containing six to ten carbons,
where one or two carbons of the alkylene, alkenylene or alkynylene
chain is optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain, the
alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
or R.sup.2 is selected from the group consisting of a bicyclic aryl
and a bicyclic heteroaryl of formula (II), as defined above, and
R.sup.3 is selected from the group consisting of aryl and
heteroaryl wherein the aryl and heteroaryl are each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9; as an
isolated stereoisomer or a mixture thereof, or a pharmaceutically
acceptable salt thereof.
54. A method of treating a disease or condition associated with Axl
activity in a mammal, wherein the method comprises administering to
the mammal either a therapeutically effective amount of a compound
of formula (I): ##STR00241## wherein: R.sup.1, R.sup.4 and R.sup.5
are each independently selected from group consisting of hydrogen,
alkyl, aryl, aralkyl, --C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7;
R.sup.2 and R.sup.3 are each independently a bicyclic aryl or a
bicyclic heteroaryl of formula (II): ##STR00242## where: A is an
alkylene chain containing six to ten carbons, an alkenylene chain
containing six to ten carbons, or an alkynylene chain containing
six to ten carbons, where one or two carbons of the alkylene,
alkenylene or alkynylene chain is optionally replaced by
--NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p is 0, 1 or
2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where each carbon
in the alkylene chain, the alkenylene chain or the alkynylene chain
is independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10, --R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
or R.sup.2 is selected from the group consisting of a bicyclic aryl
and a bicyclic heteroaryl of formula (II), as defined above, and
R.sup.3 is selected from the group consisting of aryl and
heteroaryl wherein the aryl and heteroaryl are each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; each R.sup.6 and R.sup.7 is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; each R.sup.8 is independently selected
from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); each
R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; each R.sup.10 is independently selected from the
group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; each R.sup.11 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; and each
R.sup.12 is hydrogen, alkyl, cyano, nitro or --OR.sup.9; as an
isolated stereoisomer or a mixture thereof, or a pharmaceutically
acceptable salt thereof.
55. The method of claim 54 wherein the disease or condition is
alleviated by the modulation of Axl activity.
56. The method of claim 54 wherein the disease of condition is
alleviated by a increase in Axl activity.
57. The method of claim 54 wherein the disease of condition is
alleviated by a decrease in Axl activity.
58. The method of claim 57 wherein the disease or condition is
selected from the group consisting of rheumatoid arthritis,
vascular disease, vascular injury, psoriasis, visual impairment due
to macular degeneration, diabetic retinopathy, retinopathy of
prematurity, kidney disease, osteoporosis, osteoarthritis and
cataracts.
59. The method of claim 57, wherein a manifestation of the disease
or condition is solid tumor formation in said mammal.
60. The method of claim 59, wherein the disease or condition is
selected from the group consisting of breast carcinoma, renal
carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid
carcinoma, non-small cell lung carcinoma, melanoma, prostate
carcinoma, sarcoma, gastric cancer and uveal melanoma.
61. The method of claim 57, wherein a manifestation of the disease
or condition is liquid tumor formation in said mammal.
62. The method of claim 61, wherein the disease or condition is
myeloid leukemia or lymphoma.
63. The method of claim 57 wherein the disease or condition is
endometriosis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. Provisional Patent Application No. 60/975,346, filed
Sep. 26, 2007; and U.S. Provisional Patent Application No.
60/882,769, filed Dec. 29, 2006, where these two provisional
applications are incorporated herein by reference in their
entireties.
FIELD OF THE INVENTION
[0002] This invention is directed to bicyclic aryl substituted
triazoles and bicyclic heteroaryl substituted triazoles and
pharmaceutical compositions thereof which are useful as inhibitors
of the receptor protein tyrosine kinase known as Axl. This
invention is also directed to methods of using the compounds and
compositions in treating diseases and conditions associated with
Axl activity, particularly in treating diseases and conditions
associated with angiogenesis and/or cell proliferation.
BACKGROUND OF THE INVENTION
[0003] All of the protein kinases that have been identified to date
in the human genome share a highly conserved catalytic domain of
around 300 aa. This domain folds into a bi-lobed structure in which
reside ATP-binding and catalytic sites. The complexity of protein
kinase regulation allows many potential mechanisms of inhibition
including competition with activating ligands, modulation of
positive and negative regulators, interference with protein
dimerization, and allosteric or competitive inhibition at the
substrate or ATP binding sites.
[0004] Axl (also known as UFO, ARK, and Tyro7; nucleotide accession
numbers NM.sub.--021913 and NM.sub.--001699; protein accession
numbers NP.sub.--068713 and NP.sub.--001690) is a receptor protein
tyrosine kinase (RTK) that comprises a C-terminal extracellular
ligand-binding domain and N-terminal cytoplasmic region containing
the catalytic domain. The extracellular domain of Axl has a unique
structure that juxtaposes immunoglobulin and fibronectin Type III
repeats and is reminiscent of the structure of neural cell adhesion
molecules. Axl and its two close relatives, Mer/Nyk and Sky
(Tyro3/Rse/Dtk), collectively known as the Tyro3 family of RTK's,
all bind and are stimulated to varying degrees by the same ligand,
Gas6 (growth arrest specific-6), a .about.76 kDa secreted protein
with significant homology to the coagulation cascade regulator,
Protein S. In addition to binding to ligands, the Axl extracellular
domain has been shown to undergo homophilic interactions that
mediate cell aggregation, suggesting that one important function of
Axl may be to mediate cell-cell adhesion.
[0005] Axl is predominantly expressed in the vasculature in both
endothelial cells (EC's) and vascular smooth muscle cells (VSMC's)
and in cells of the myeloid lineage and is also detected in breast
epithelial cells, chondrocytes, Sertoli cells and neurons. Several
functions including protection from apoptosis induced by serum
starvation, TNF-.alpha. or the viral protein E1A, as well as
migration and cell differentiation have been ascribed to Axl
signaling in cell culture. However, Axl-/- mice exhibit no overt
developmental phenotype and the physiological function of Axl in
vivo is not clearly established in the literature.
[0006] Angiogenesis (the formation of new blood vessels) is limited
to functions such as wound healing and the female reproductive
cycle in healthy adults. This physiological process has been
co-opted by tumors, thus securing an adequate blood supply that
feeds tumor growth and facilitates metastasis. Deregulated
angiogenesis also a feature of many other diseases (for example,
psoriasis, rheumatoid arthritis, endometriosis and blindness due to
age-related macular degeneration (AMD), retinopathy of prematurity
and diabetes) and often contributes to the progression or pathology
of the condition.
[0007] The overexpression of Axl and/or its ligand has also been
reported in a wide variety of solid tumor types including, but not
limited to, breast, renal, endometrial, ovarian, thyroid, non-small
cell lung carcinoma, and uveal melanoma as well as in myeloid
leukemia's. Furthermore, it possesses transforming activity in
NIH3T3 and 32D cells. It has been demonstrated that loss of Axl
expression in tumor cells blocks the growth of solid human
neoplasms in an in vivo MDA-MB-231 breast carcinoma xenograft
model. Taken together, these data suggest Axl signaling can
independently regulate EC angiogenesis and tumor growth and thus
represents a novel target class for tumor therapeutic
development.
[0008] The expression of Axl and Gas6 proteins is upregulated in a
variety of other disease states including endometriosis, vascular
injury and kidney disease and Axl signaling is functionally
implicated in the latter two indications. Axl-Gas6 signaling
amplifies platelet responses and is implicated in thrombus
formation. Axl may thus potentially represent a therapeutic target
for a number of diverse pathological conditions including solid
tumors, including, but not limited to, breast, renal, endometrial,
ovarian, thyroid, non-small cell lung carcinoma and uveal melanoma;
liquid tumors, including but not limited to, leukemias
(particularly myeloid leukemias) and lymphomas; endometriosis,
vascular disease/injury (including but not limited to restenosis,
atherosclerosis and thrombosis), psoriasis; visual impairment due
to macular degeneration; diabetic retinopathy and retinopathy of
prematurity; kidney disease (including but not limited to
glomerulonephritis, diabetic nephropathy and renal transplant
rejection), rheumatoid arthritis; osteoporosis, osteoarthritis and
cataracts.
SUMMARY OF THE INVENTION
[0009] This invention is directed to certain bicyclic aryl
substituted triazoles and certain bicyclic heteroaryl substituted
triazoles which are useful as Axl inhibitors, methods of using such
compounds in treating diseases and conditions associated with Axl
activity and pharmaceutical compositions comprising such
compounds.
[0010] Accordingly, in one aspect this invention is directed to a
compound of formula (I):
##STR00001##
wherein: [0011] R.sup.1, R.sup.4 and R.sup.5 are each independently
selected from group consisting of hydrogen, alkyl, aryl, aralkyl,
--C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7; [0012] R.sup.2 and
R.sup.3 are each independently a bicyclic aryl or a bicyclic
heteroaryl of formula (II):
[0012] ##STR00002## [0013] where: [0014] A is an alkylene chain
containing six to ten carbons, an alkenylene chain containing six
to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0015] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
[0016] or R.sup.2 is selected from the group consisting of a
bicyclic aryl and a bicyclic heteroaryl of formula (II), as defined
above, and R.sup.3 is selected from the group consisting of aryl
and heteroaryl wherein the aryl and heteroaryl are each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0017] or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; [0018] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0019] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0020]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; [0021] each R.sup.10 is independently selected
from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; [0022] each
R.sup.11 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain, an
optionally substituted straight or branched alkenylene chain and an
optionally substituted straight or branched alkynylene chain; and
[0023] each R.sup.12 is hydrogen, alkyl, cyano, nitro or
--OR.sup.9; as an isolated stereoisomer or a mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0024] In another aspect, this invention is directed to
pharmaceutical compositions comprising a pharmaceutically
acceptable excipient and a compound of formula (I), as described
above, as an isolated stereoisomer or mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0025] In another aspect, this invention is directed to methods of
treating a disease or condition associated with Axl activity in a
mammal, wherein the methods comprise administering to the mammal a
therapeutically effective amount of a compound of formula (I), as
described above, as an isolated stereoisomer or mixture thereof, or
a pharmaceutically acceptable salt thereof, or a therapeutically
effective amount of a pharmaceutical composition comprising a
pharmaceutically acceptable excipient and a compound of formula
(I), as described above, as an isolated stereoisomer or mixture
thereof, or a pharmaceutically acceptable salt thereof.
[0026] In another aspect, this invention provides assays to
determine a compound of the invention effectiveness in inhibiting
Axl activity in a cell-based assay.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0027] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0028] "Amino" refers to the --NH.sub.2 radical.
[0029] "Carboxy" refers to the --C(O)OH radical.
[0030] "Cyano" refers to the --CN radical.
[0031] "Nitro" refers to the --NO.sub.2 radical.
[0032] "Oxa" refers to the --O-- radical.
[0033] "Oxo" refers to the .dbd.O radical.
[0034] "Thioxo" refers to the .dbd.S radical.
[0035] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to twelve carbon atoms, preferably
one to eight carbon atoms or one to six carbon atoms ("lower
alkyl"), and which is attached to the rest of the molecule by a
single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl
(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),
3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise
specifically in the specification, an alkyl radical may be
optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl,
--OR.sup.20, --OC(O)--R.sup.20, --N(R.sup.20).sub.2,
--C(O)R.sup.20, --C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.20, --N(R.sup.20)C(O)R.sup.20,
--N(R.sup.20)S(O).sub.tR.sup.20 (where t is 1 or 2),
--S(O).sub.tOR.sup.20 (where t is 1 or 2), --S(O).sub.pR.sup.20
(where p is 0, 1 or 2), and --S(O).sub.tN(R.sup.20).sub.2 (where t
is 1 or 2) where each R.sup.20 is independently hydrogen, alkyl,
haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0036] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
at least one double bond, having from two to twelve carbon atoms,
preferably one to eight carbon atoms and which is attached to the
rest of the molecule by a single bond, for example, ethenyl,
prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the
like. Unless stated otherwise specifically in the specification, an
alkenyl radical may be optionally substituted by one or more of the
following substituents: halo, cyano, nitro, oxo, thioxo,
trimethylsilanyl, --OR.sup.20, --OC(O)--R.sup.20,
--N(R.sup.20).sub.2, --C(O)R.sup.20, --C(O)OR.sup.20,
--C(O)N(R.sup.20).sub.2, --N(R.sup.20)C(O)OR.sup.20,
--N(R.sup.20)C(O)R.sup.20, --N(R.sup.20)S(O).sub.tR.sup.20 (where t
is 1 or 2), --S(O).sub.tOR.sup.20 (where t is 1 or 2),
--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2) where each
R.sup.20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0037] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
at least one triple bond, optionally containing at least one double
bond, having from two to twelve carbon atoms, preferably one to
eight carbon atoms and which is attached to the rest of the
molecule by a single bond, for example, ethynyl, propynyl, butynyl,
pentynyl, hexynyl, and the like. Unless stated otherwise
specifically in the specification, an alkynyl radical may be
optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl,
--OR.sup.20, --OC(O)--R.sup.20, --N(R.sup.20).sub.2,
--C(O)R.sup.20,
--C(O)OR.sup.20--C(O)N(R.sup.20).sub.2--N(R.sup.20)C(O)OR.sup.20,
--N(R.sup.20)C(O)R.sup.20, --N(R.sup.20)S(O).sub.tR.sup.20 (where t
is 1 or 2), --S(O).sub.tOR.sup.20 (where t is 1 or 2),
--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2) where each
R.sup.20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0038] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing no unsaturation and having from one to twelve
carbon atoms, for example, methylene, ethylene, propylene,
n-butylene, and the like. The alkylene chain is attached to the
rest of the molecule through a single bond and to the radical group
through a single bond. The points of attachment of the alkylene
chain to the rest of the molecule and to the radical group can be
through one carbon in the alkylene chain or through any two carbons
within the chain. Unless stated otherwise specifically in the
specification, an alkylene chain may be optionally substituted by
one or more of the following substituents: halo, cyano, nitro,
aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,
trimethylsilanyl, --OR.sup.20, --OC(O)--R.sup.20,
--N(R.sup.20).sub.2, --C(O)R.sup.20, --C(O)OR.sup.20,
--C(O)N(R.sup.20).sub.2, --N(R.sup.20)C(O)OR.sup.20,
--N(R.sup.20)C(O)R.sup.20, --N(R.sup.20)S(O).sub.tR.sup.20 (where t
is 1 or 2), --S(O).sub.tOR.sup.20 (where t is 1 or 2),
--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2) where each
R.sup.20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0039] "Alkenylene" or "alkenylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one double bond and having from two
to twelve carbon atoms, for example, ethenylene, propenylene,
n-butenylene, and the like. The alkenylene chain is attached to the
rest of the molecule through a double bond or a single bond and to
the radical group through a double bond or a single bond. The
points of attachment of the alkenylene chain to the rest of the
molecule and to the radical group can be through one carbon or any
two carbons within the chain. Unless stated otherwise specifically
in the specification, an alkenylene chain may be optionally
substituted by one or more of the following substituents: halo,
cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo,
thioxo, trimethylsilanyl, --OR.sup.20, --OC(O)--R.sup.20,
--N(R.sup.20).sub.2, --C(O)R.sup.20, --C(O)OR.sup.20,
--C(O)N(R.sup.20).sub.2, --N(R.sup.20)C(O)OR.sup.20,
--N(R.sup.20)C(O)R.sup.20, --N(R.sup.20)S(O).sub.tR.sup.20 (where t
is 1 or 2), --S(O).sub.tOR.sup.20 (where t is 1 or 2),
--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2) where each
R.sup.20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0040] "Alkynylene" or "alkynylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one triple bond and having from two
to twelve carbon atoms, for example, propynylene, n-butenylene, and
the like. The alkynylene chain is attached to the rest of the
molecule through a single bond and to the radical group through a
double bond or a single bond. The points of attachment of the
alkynylene chain to the rest of the molecule and to the radical
group can be through one carbon or any two carbons within the
chain. Unless stated otherwise specifically in the specification,
an alkynylene chain may be optionally substituted by one or more of
the following substituents: alkyl, alkenyl, halo, haloalkenyl,
cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo,
thioxo, trimethylsilanyl, --OR.sup.20, --OC(O)--R.sup.20,
--N(R.sup.20).sub.2, --C(O)R.sup.20, --C(O)OR.sup.20,
--C(O)N(R.sup.20).sub.2, --N(R.sup.20)C(O)OR.sup.20,
--N(R.sup.20)C(O)R.sup.20, --N(R.sup.20)S(O).sub.tR.sup.20 (where t
is 1 or 2), --S(O).sub.tOR.sup.20 (where t is 1 or 2),
--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2) where each
R.sup.20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0041] "Alkoxy" refers to a radical of the formula --OR.sub.a where
R.sub.a is an alkyl radical as defined above containing one to
twelve carbon atoms. The alkyl part of the alkoxy radical may be
optionally substituted as defined above for an alkyl radical.
[0042] "Alkoxyalkyl" refers to a radical of the formula
--R.sub.b--O--R.sub.a where R.sub.a is an alkyl radical as defined
above and R.sub.b is an alkylene chain as defined above. The oxygen
atom may be bonded to any carbon in the alkyl radical or the
alkylene chain. The alkyl part of the alkoxyalkyl radical may be
optionally substituted as defined above for an alkyl radical and
the alkylene chain part of the alkoxyalkyl radical may be
optionally substituted as defined above for an alkylene chain.
[0043] "Aryl" refers to a hydrocarbon ring system radical
comprising hydrogen, 6 to 14 carbon atoms and at least one aromatic
ring. For purposes of this invention, the aryl radical may be a
monocyclic, bicyclic, or tricyclic system and which may include
spiro ring systems. An aryl radical is commonly, but not
necessarily, attached to the parent molecule via an aromatic ring
of the aryl radical. For purposes of this invention, an "aryl"
radical as defined herein can not contain rings having more than 7
members and cannot contain rings wherein two non-adjacent members
thereof are connected through an atom or a group of atoms (i.e., a
bridged ring system). Aryl radicals include, but are not limited
to, aryl radicals derived from acenaphthylene, anthracene, azulene,
benzene, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, fluorene,
as-indacene, s-indacene, indane, indene, naphthalene, phenalene,
and phenanthrene. Unless stated otherwise specifically in the
specification, the term "optionally substituted aryl" is meant to
include aryl radicals optionally substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.21--OR.sup.20,
--R.sup.21--OC(O)--R.sup.20, --R.sup.21--N(R.sup.20).sub.2,
--R.sup.21--C(O)R.sup.20, --R.sup.21--C(O)OR.sup.20,
--R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--O--R.sup.22--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2), where
each R.sup.20 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, may optionally form an optionally substituted
N-heterocyclyl or an optionally substituted N-heteroaryl, each
R.sup.21 is independently a direct bond or a straight or branched
alkylene or alkenylene chain, and R.sup.22 is a straight or
branched alkylene or alkenylene chain.
[0044] "Aralkyl" refers to a radical of the formula
--R.sub.b--R.sub.c where R.sub.b is an alkylene chain as defined
above and R.sub.c is one or more aryl radicals as defined above,
for example, benzyl, diphenylmethyl and the like. The alkylene
chain part of the aralkyl radical may be optionally substituted as
described above for an alkylene chain. The aryl part of the aralkyl
radical may be optionally substituted as described above for an
aryl.
[0045] "Aralkenyl" refers to a radical of the formula
--R.sub.d--R.sub.c where R.sub.d is an alkenylene chain as defined
above and R.sub.c is one or more aryl radicals as defined above.
The aryl part of the aralkenyl radical may be optionally
substituted as described above for an aryl. The alkenylene chain
part of the aralkenyl radical may be optionally substituted as
defined above for an alkenylene group.
[0046] "Aralkynyl" refers to a radical of the formula
--R.sub.eR.sub.c where R.sub.e is an alkynylene chain as defined
above and R.sub.c is one or more aryl radicals as defined above.
The aryl part of the aralkynyl radical may be optionally
substituted as described above for an aryl. The alkynylene chain
part of the aralkynyl radical may be optionally substituted as
defined above for an alkynylene chain.
[0047] "Aryloxy" refers to a radical of the formula --OR.sub.c
where R.sub.c is an aryl as defined above. The aryl part of the
aryloxy radical may be optionally substituted as defined above.
[0048] "Aralkyloxy" refers to a radical of the formula --OR.sub.f
where R.sub.f is an aralkyl radical as defined above. The aralkyl
part of the aralkyloxy radical may be optionally substituted as
defined above.
[0049] "Cycloalkyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which may include spiro or bridged ring systems,
having from three to fifteen carbon atoms, preferably having from
three to ten carbon atoms, more preferably from five to seven
carbons and which is saturated or unsaturated and attached to the
rest of the molecule by a single bond. For purposes of this
invention, a bridged ring system is a system wherein two
non-adjacent ring atoms thereof are connected through an atom or a
group of atoms. Monocyclic cycloalkyl radicals include non-bridged
cycloalkyl radicals, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic
radicals include fused, spiro or bridged cycloalkyl radicals, for
example, C.sub.10 radicals such as adamantanyl (bridged) and
decalinyl (fused), and C.sub.7 radicals such as
bicyclo[3.2.0]heptanyl (fused), norbornanyl and norbornenyl
(bridged), as well as substituted polycyclic radicals, for example,
substituted C.sub.7 radicals such as
7,7-dimethylbicyclo[2.2.1]heptanyl (bridged), and the like. Unless
otherwise stated specifically in the specification, the term
"optionally substituted cycloalkyl" is meant to include cycloalkyl
radicals which are optionally substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.21--OR.sup.20,
--R.sup.21--OC(O)--R.sup.20, --R.sup.21--N(R.sup.20).sub.2,
--R.sup.21--C(O)R.sup.20, --R.sup.21--C(O)OR.sup.20,
--R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2), where
each R.sup.20 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, may optionally form an optionally substituted
N-heterocyclyl or an optionally substituted N-heteroaryl, and each
R.sup.21 is independently a direct bond or a straight or branched
alkylene or alkenylene chain.
[0050] "Cycloalkylalkyl" refers to a radical of the formula
--R.sub.bR.sub.g where R.sub.b is an alkylene chain as defined
above and R.sub.g is a cycloalkyl radical as defined above. The
alkylene chain and the cycloalkyl radical may be optionally
substituted as defined above.
[0051] "Cycloalkylalkenyl" refers to a radical of the formula
--R.sub.dR.sub.g where R.sub.d is an alkenylene chain as defined
above and R.sub.g is a cycloalkyl radical as defined above. The
alkenylene chain and the cycloalkyl radical may be optionally
substituted as defined above.
[0052] "Cycloalkylalkynyl" refers to a radical of the formula
--R.sub.eR.sub.g where R.sub.e is an alkynylene radical as defined
above and R.sub.g is a cycloalkyl radical as defined above. The
alkynylene chain and the cycloalkyl radical may be optionally
substituted as defined above.
[0053] "Halo" refers to bromo, chloro, fluoro or iodo.
[0054] "Haloalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
for example, trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
The alkyl part of the haloalkyl radical may be optionally
substituted as defined above for an alkyl radical.
[0055] "Haloalkoxy" refers to an alkoxy radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
for example, trifluoromethoxy, difluoromethoxy, trichloromethoxy,
2,2,2-trifluoroethoxy, and the like. The alkoxy part of the
haloalkoxy radical may be optionally substituted as defined above
for an alkoxy radical.
[0056] "Haloalkenyl" refers to an alkenyl radical, as defined
above, that is substituted by one or more halo radicals, as defined
above. The alkenyl part of the haloalkyl radical may be optionally
substituted as defined above for an alkenyl radical.
[0057] "Haloalkynyl" refers to an alkynyl radical, as defined
above, that is substituted by one or more halo radicals, as defined
above. The alkynyl part of the haloalkyl radical may be optionally
substituted as defined above for an alkynyl radical.
[0058] "Heterocyclyl" refers to a stable 3- to 18-membered
non-aromatic ring radical which comprises one to twelve carbon
atoms and from one to six heteroatoms selected from the group
consisting of nitrogen, oxygen and sulfur. Unless stated otherwise
specifically in the specification, the heterocyclyl radical may be
a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which
may include spiro or bridged ring systems; and the nitrogen, carbon
or sulfur atoms in the heterocyclyl radical may be optionally
oxidized; the nitrogen atom may be optionally quaternized; and the
heterocyclyl radical may be partially or fully saturated. Examples
of such heterocyclyl radicals include, but are not limited to,
dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
octahydroindolyl, octahydroisoindolyl,
octahydro-1H-pyrrolo[3,2-c]pyridinyl,
octahydro-1H-pyrrolo[2,3-c]pyridinyl,
octahydro-1H-pyrrolo[2,3-b]pyridinyl,
octahydro-1H-pyrrolo[3,4-b]pyridinyl,
octahydropyrrolo[3,4-c]pyrrolyl,
octahydro-1H-pyrido[1,2-a]pyrazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
quinuclidinyl, thiazolidinyl, tetrahydrofuryl,
thienyl[1,3]dithianyl, trithianyl, tetrahydropyranyl,
thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,
1,1-dioxo-thiomorpholinyl, azetidinyl,
octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl,
decahydroprazino[1,2-a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl,
and 2,7-diazaspiro[4.4]nonanyl. Unless stated otherwise
specifically in the specification, the term "optionally substituted
heterocyclyl" is meant to include heterocyclyl radicals as defined
above which are optionally substituted by one or more substituents
selected from the group consisting of alkyl, alkenyl, alkynyl,
halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.21--OR.sup.20, --R.sup.21--OC(O)--R.sup.20,
--R.sup.21--N(R.sup.20).sub.2, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)OR.sup.20, --R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2), where
each R.sup.20 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, may optionally form an optionally substituted
N-heterocyclyl or an optionally substituted N-heteroaryl, and each
R.sup.21 is independently a direct bond or a straight or branched
alkylene or alkenylene chain.
[0059] "N-heterocyclyl" refers to a heterocyclyl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heterocyclyl radical to the rest of the molecule
is through a nitrogen atom in the heterocyclyl radical. An
N-heterocyclyl radical may be optionally substituted as described
above for heterocyclyl radicals.
[0060] "Heterocyclylalkyl" refers to a radical of the formula
--R.sub.bR.sub.h where R.sub.b is an alkylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
if the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkyl radical at the nitrogen
atom. The alkylene chain of the heterocyclylalkyl radical may be
optionally substituted as defined above for an alkyene chain. The
heterocyclyl part of the heterocyclylalkyl radical may be
optionally substituted as defined above for a heterocyclyl
radical.
[0061] "Heterocyclylalkenyl" refers to a radical of the formula
--R.sub.dR.sub.h where R.sub.d is an alkenylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
if the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkenylene chain at the
nitrogen atom. The alkenylene chain of the heterocyclylalkenyl
radical may be optionally substituted as defined above for an
alkenylene chain. The heterocyclyl part of the heterocyclylalkenyl
radical may be optionally substituted as defined above for a
heterocyclyl radical.
[0062] "Heterocyclylalkynyl" refers to a radical of the formula
--R.sub.eR.sub.h where R.sub.e is an alkynylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
if the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkynyl radical at the nitrogen
atom. The alkynylene chain part of the heterocyclylalkynyl radical
may be optionally substituted as defined above for an alkynylene
chain. The heterocyclyl part of the heterocyclylalkynyl radical may
be optionally substituted as defined above for a heterocyclyl
radical.
[0063] "Heteroaryl" refers to a 5- to 14-membered ring system
radical comprising hydrogen atoms, one to thirteen carbon atoms,
one to six heteroatoms selected from the group consisting of
nitrogen, oxygen and sulfur, and at least one aromatic ring. A
heteroaryl radical is commonly, but not necessarily, attached to
the parent molecule via an aromatic ring of the heteroaryl radical.
For purposes of this invention, the heteroaryl radical may be a
monocyclic, bicyclic or tricyclic ring system, which may include
spiro ring systems; and the nitrogen, carbon or sulfur atoms in the
heteroaryl radical may be optionally oxidized; the nitrogen atom
may be optionally quaternized. For purposes of this invention, the
aromatic ring of the heteroaryl radical need not contain a
heteroatom, as long as one ring of the heteroaryl radical contains
a heteroatom. For example, 1,2,3,4-tetrahydroisoquinolin-7-yl is
considered a "heteroaryl" for the purposes of this invention. For
purposes of this invention, a "heteroaryl" radical as defined
herein can not contain rings having more than 7 members and cannot
contain rings wherein two non-adjacent members thereof are
connected through an atom or a group of atoms (i.e., a bridged ring
system). Examples of heteroaryl radicals include, but are not
limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl,
1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
7',8'-dihydro-5H-spiro[[1,3]dioxolane-2,6'-quinoline]-3'-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
furo[3,2-c]pyridinyl, furopyrimidinyl, furopyridazinyl,
furopyrazinyl, isothiazolyl, imidazolyl, imidazopyrimidinyl,
imidazopyridazinyl, imidazopyrazinyl, indazolyl, indolyl,
indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl
(isoquinolyl), indolizinyl, isoxazolyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, phenanthridinyl, pteridinyl, purinyl, pyrrolyl,
pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl (pyridyl),
pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,
pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl, pyrrolopyrimidinyl,
pyrrolopyridazinyl, pyrrolopyrazinyl, quinazolinyl, quinoxalinyl,
quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl,
5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl,
3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, triazolyl, tetrazolyl,
1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl,
thieno[2,3-d]pyrimidinyl, thienopyrimidinyl (e.g.,
thieno[3,2-d]pyrimidinyl), thieno[2,3-c]pyridinyl,
thienopyridazinyl, thienopyrazinyl, and thiophenyl (thienyl).
Unless stated otherwise specifically in the specification, the term
"optionally substituted heteroaryl" is meant to include heteroaryl
radicals as defined above which are optionally substituted by one
or more substituents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.21--OR.sup.20,
--R.sup.21--OC(O)--R.sup.20, --R.sup.21--N(R.sup.20).sub.2,
--R.sup.21--C(O)R.sup.20, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2), where
each R.sup.20 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, may optionally form an optionally substituted
N-heterocyclyl or an optionally substituted N-heteroaryl, and each
R.sup.21 is independently a direct bond or a straight or branched
alkylene or alkenylene chain.
[0064] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl
radical may be optionally substituted as described above for
heteroaryl radicals.
[0065] "Heteroarylalkyl" refers to a radical of the formula
--R.sub.bR.sub.i where R.sub.b is an alkylene chain as defined
above and R.sub.i is a heteroaryl radical as defined above. The
heteroaryl part of the heteroarylalkyl radical may be optionally
substituted as defined above for a heteroaryl. The alkylene chain
part of the heteroarylalkyl radical may be optionally substituted
as defined above for an alkylene chain.
[0066] "Heteroarylalkenyl" refers to a radical of the formula
--R.sub.dR.sub.i where R.sub.d is an alkenylene chain as defined
above and R.sub.i is a heteroaryl radical as defined above. The
heteroaryl part of the heteroarylalkenyl radical may be optionally
substituted as defined above for a heteroaryl. The alkenylene chain
part of the heteroarylalkenyl radical may be optionally substituted
as defined above for an alkenylene chain.
[0067] "Heteroarylalkynyl" refers to a radical of the formula
--R.sub.eR.sub.i where R.sub.e is an alkynylene chain as defined
above and R.sub.i is a heteroaryl radical as defined above. The
heteroaryl part of the heteroarylalkynyl radical may be optionally
substituted as defined above for a heteroaryl. The alkynylene chain
part of the heteroarylalkynyl radical may be optionally substituted
as defined above for an alkynylene chain.
[0068] "Hydroxyalkyl" refers to an alkyl radical as defined above
which is substituted by one or more hydroxy radicals (--OH).
[0069] "Hydroxyalkenyl" refers to an alkenyl radical as defined
above which is substituted by one or more hydroxy radicals
(--OH).
[0070] "Hydroxyalkenyl" refers to an alkynyl radical as defined
above which is substituted by one or more hydroxy radicals
(--OH).
[0071] Certain chemical groups named herein may be preceded by a
shorthand notation indicating the total number of carbon atoms that
are to be found in the indicated chemical group. For example;
C.sub.7-C.sub.12alkyl describes an alkyl group, as defined below,
having a total of 7 to 12 carbon atoms, and
C.sub.4-C.sub.12cycloalkylalkyl describes a cycloalkylalkyl group,
as defined below, having a total of 4 to 12 carbon atoms. The total
number of carbons in the shorthand notation does not include
carbons that may exist in substituents of the group described.
[0072] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0073] "Mammal" includes humans and domestic animals, such as cats,
dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
Preferably, for purposes of this invention, the mammal is a
human.
[0074] "Optional" or "optionally" means that the subsequently
described event or circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution. When a
functional group is described as "optionally substituted," and in
turn, substitutents on the functional group are also "optionally
substituted", and so on, for the purposes of this invention, such
iterations are limited to five, preferably such iterations are
limited to two.
[0075] "Pharmaceutically acceptable excipient" includes without
limitation any adjuvant, carrier, excipient, glidant, sweetening
agent, diluent, preservative, dye/colorant, flavor enhancer,
surfactant, wetting agent, dispersing agent, suspending agent,
stabilizer, isotonic agent, solvent, or emulsifier which has been
approved by the United States Food and Drug Administration as being
acceptable for use in humans or domestic animals.
[0076] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0077] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but not limited to, hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfonic acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0078] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Preferred inorganic
salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived from organic bases include, but are not
limited to, salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,
lysine, arginine, histidine, caffeine, procaine, hydrabamine,
choline, betaine, benethamine, benzathine, ethylenediamine,
glucosamine, methylglucamine, theobromine, triethanolamine,
tromethamine, purines, piperazine, piperidine, N-ethylpiperidine,
polyamine resins and the like. Particularly preferred organic bases
are isopropylamine, diethylamine, ethanolamine, trimethylamine,
dicyclohexylamine, choline and caffeine.
[0079] A "pharmaceutical composition" refers to a formulation of a
compound of the invention and a medium generally accepted in the
art for the delivery of the biologically active compound to
mammals, for example, humans. Such a medium includes all
pharmaceutically acceptable carriers, diluents or excipients
therefor.
[0080] "Therapeutically effective amount" refers to that amount of
a compound of the invention which, when administered to a mammal,
preferably a human, is sufficient to effect treatment, as defined
below, of a disease or condition of interest in the mammal,
preferably a human. The amount of a compound of the invention which
constitutes a "therapeutically effective amount" will vary
depending on the compound, the disease or condition and its
severity, and the age of the mammal to be treated, but can be
determined routinely by one of ordinary skill in the art having
regard to his own knowledge and to this disclosure.
[0081] "Treating" or "treatment" as used herein covers the
treatment of the disease or condition of interest in a mammal,
preferably a human, having the disease or condition of interest,
and includes:
[0082] (i) preventing the disease or condition from occurring in a
mammal, in particular, when such mammal is predisposed to the
condition but has not yet been diagnosed as having it;
[0083] (ii) inhibiting the disease or condition, i.e., arresting
its development;
[0084] (iii) relieving the disease or condition, i.e., causing
regression of the disease or condition; or
[0085] (iv) stabilizing the disease or condition.
[0086] As used herein, the terms "disease" and "condition" may be
used interchangeably or may be different in that the particular
malady or condition may not have a known causative agent (so that
etiology has not yet been worked out) and it is therefore not yet
recognized as a disease but only as an undesirable condition or
syndrome, wherein a more or less specific set of symptoms have been
identified by clinicians.
[0087] The compounds of the invention, or their pharmaceutically
acceptable salts may contain one or more asymmetric centres and may
thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino
acids. The present invention is meant to include all such possible
isomers, as well as their racemic and optically pure forms.
Optically active (+) and (-), (R)- and (S)-, or (D)- and
(L)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques, such as HPLC
using a chiral column. When the compounds described herein contain
olefinic double bonds or other centres of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are also intended to be included.
[0088] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0089] A "tautomer" refers to a proton shift from one atom of a
molecule to another atom of the same molecule. The present
invention includes tautomers of any said compounds.
[0090] "Atropisomers" are stereoisomers resulting from hindered
rotation about single bonds where the barrier to rotation is high
enough to allow for the isolation of the conformers (Eliel, E. L.;
Wilen, S. H. Stereochemistry of Organic Compounds; Wiley &
Sons: New York, 1994; Chapter 14). Atropisomerism is significant
because it introduces an element of chirality in the absence of
stereogenic atoms. The invention is meant to encompass
atropisomers, for example in cases of limited rotation around the
single bonds emanating from the core triazole structure,
atropisomers are also possible and are also specifically included
in the compounds of the invention.
[0091] The chemical naming protocol and structure diagrams used
herein are a modified form of the I.U.P.A.C. nomenclature system
wherein the compounds of the invention are named herein as
derivatives of the central core structure, i.e., the triazole
structure. For complex chemical names employed herein, a
substituent group is named before the group to which it attaches.
For example, cyclopropylethyl comprises an ethyl backbone with
cyclopropyl substituent. In chemical structure diagrams, all bonds
are identified, except for some carbon atoms, which are assumed to
be bonded to sufficient hydrogen atoms to complete the valency.
[0092] For purposes of this invention, the depiction of the bond
attaching the R.sup.3 substituent to the parent triazole moiety in
formula (I), as shown below:
##STR00003##
is intended to include only the two regioisomers shown below, i.e.,
compounds of formula (Ia) and (Ib):
##STR00004##
[0093] The numbering system of the ring atoms in compounds of
formula (Ia) is shown below:
##STR00005##
[0094] For example, a compound of formula (Ia) wherein R.sup.1 is
hydrogen, R.sup.2 is
3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl, R.sup.4 and
R.sup.4 are both hydrogen, and R.sup.3 is
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl; i.e., a compound
of the following formula:
##STR00006##
is named herein as
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine.
[0095] The numbering system of the ring atoms in compounds of
formula (Ib) is shown below:
##STR00007##
Compounds of formula (Ib) are similarly named herein.
EMBODIMENTS OF THE INVENTION
[0096] Of the various aspects of the invention, as set forth above
in the Summary of the Invention, certain embodiments are
preferred.
[0097] Accordingly, one embodiment is wherein the compound of
formula (I) is a compound of formula (Ia):
##STR00008##
wherein: [0098] R.sup.1, R.sup.4 and R.sup.5 are each independently
selected from group consisting of hydrogen, alkyl, aryl, aralkyl,
--C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7; [0099] R.sup.2 and
R.sup.3 are each independently a bicyclic aryl or a bicyclic
heteroaryl of formula (II):
[0099] ##STR00009## [0100] where: [0101] A is an alkylene chain
containing six to ten carbons, an alkenylene chain containing six
to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0102] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
[0103] or R.sup.2 is selected from the group consisting of a
bicyclic aryl and a bicyclic heteroaryl of formula (II), as defined
above, and R.sup.3 is selected from the group consisting of aryl
and heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0104] or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; [0105] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0106] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0107]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; [0108] each R.sup.10 is independently selected
from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; [0109] each
R.sup.11 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain, an
optionally substituted straight or branched alkenylene chain and an
optionally substituted straight or branched alkynylene chain; and
[0110] each R.sup.12 is hydrogen, alkyl, cyano, nitro or
--OR.sup.9; as an isolated stereoisomer or a mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0111] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0112]
R.sup.1, R.sup.4 and R.sup.5 are each independently selected from
group consisting of hydrogen, alkyl, aryl, aralkyl, --C(O)R.sup.9
and --C(O)N(R.sup.6)R.sup.7; [0113] R.sup.2 is a bicyclic aryl or a
bicyclic heteroaryl of formula (II):
[0113] ##STR00010## [0114] where: [0115] A is an alkylene chain
containing six to ten carbons, an alkenylene chain containing six
to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0116] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0117] R.sup.3 is selected
from the group consisting of aryl and heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14--, R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0118] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0119] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0120]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; [0121] each R.sup.10 is independently selected
from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; [0122] each
R.sup.11 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain, an
optionally substituted straight or branched alkenylene chain and an
optionally substituted straight or branched alkynylene chain; and
[0123] each R.sup.12 is hydrogen, alkyl, cyano, nitro or
--OR.sup.9.
[0124] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0125]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0126] R.sup.2 is a
bicyclic aryl of formula (II):
##STR00011##
[0126] where: [0127] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0128] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0129] R.sup.3 is a monocyclic aryl or a
monocyclic heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.15--OR.sup.14, --R.sup.15--C(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0130] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0131] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0132]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0133] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0134] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0135] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0136]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0137] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00012##
[0137] where: [0138] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0139] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0140] R.sup.3 is a
monocyclic aryl or a monocyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0141] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0142] each R.sup.18
is independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0143]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0144] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0145] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0146] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0147]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0148] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00013##
[0148] where: [0149] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0150] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0151] R.sup.3 is a
monocyclic aryl optionally substituted by one or more substitutents
selected from the group consisting of alkyl, alkenyl, halo,
haloalkyl, haloalkenyl, cyano, nitro, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O)R.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0152] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0153] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0154]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0155] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0156] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0157] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0158]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0159] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00014##
[0159] where: [0160] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0161] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0162] R.sup.3 is monocyclic heteroaryl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0163] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0164] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0165]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0166] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0167] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0168] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0169]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0170] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00015##
[0170] where: [0171] A is an alkylene chain containing six carbons,
where one carbon of the alkylene chain is replaced by --NR.sup.9--
and where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0172] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0173] R.sup.3 is monocyclic heteroaryl
selected from the group consisting of furanyl, pyranyl, pyridinyl,
pyrimidinyl and pyridazinyl, each optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl, aryl,
and aralkyl and each R.sup.15 is independently a direct bond or a
straight or branched alkylene chain; [0174] each R.sup.6 and
R.sup.7 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, hydroxyalkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2;
[0175] each R.sup.8 is independently selected from the group
consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, --R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0176]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, and optionally substituted heteroarylalkyl; [0177] each
R.sup.10 is independently selected from the group consisting of a
direct bond and an optionally substituted straight or branched
alkylene chain; and [0178] each R.sup.11 is an optionally
substituted straight or branched alkylene chain.
[0179] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) which is
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-9-yl)-1-(5-(tr-
ifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine.
[0180] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0181]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0182] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00016##
[0182] where: [0183] A is an alkylene chain containing six carbons,
where at least one carbon of the alkylene chain is replaced by
--NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p is 0, 1 or
2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where each carbon
in the alkylene chain is independently optionally substituted by
one or two substituents selected from the group consisting of oxo,
thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl,
cycloalkylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0184] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0185] R.sup.3 is a bicyclic heteroaryl
selected from the group consisting of benzothiazolyl, benzofuranyl,
indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl,
quinazolinyl, quinoxalinyl, imidazopyrimidinyl, pyrrolopyrimidinyl,
furopyrimidinyl, thienopyrimidinyl, thienopyridazinyl,
furopyridazinyl, pyrrolopyridazinyl, imidazopyridazinyl,
thienopyrazinyl, furopyrazinyl, pyrrolopyrazinyl and
imidazopyridinyl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--C(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0186] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0187] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0188]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0189] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0190] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0191] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0192]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0193] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00017##
[0193] where: [0194] A is an alkylene chain containing six carbons,
where at least one carbon of the alkylene chain is replaced by
--NR.sup.9-- or --O-- and where each carbon in the alkylene chain
is independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0195] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0196] R.sup.3 is a bicyclic heteroaryl
selected from the group consisting of thienopyrimidinyl,
quinazolinyl and benzothiazolyl, each optionally substituted by one
or more substitutents selected from the group consisting of alkyl,
alkenyl, halo, haloalkyl, oxo, thioxo, cyano, nitro,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0197] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0198] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0199]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0200] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0201] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0202] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) selected from the
group consisting of: [0203]
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-(6-flu-
oroquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine; [0204]
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenz-
o[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine; [0205]
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenz-
o[d]azocin-9-yl)-1H-1,2,4-triazole-3,5-diamine; [0206]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(2,3,4,5-tetrahy-
drobenzo[b][1,4]dioxocin-8-yl)-1H-1,2,4-triazole-3,5-diamine;
[0207]
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydro-benzo[d]azocin-8-yl)-1-(6,7--
dimethoxy-quinazolin-4-yl)-1H-[1,2,4]triazole-3,5-diamine; [0208]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(3-cyclopentyl-1-
,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine;
[0209]
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[-
d]azocin-8-yl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-t-
riazole-3,5-diamine; [0210]
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azoci-
n-8-yl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
[0211]
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-
-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
[0212]
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[-
d]azocin-8-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3-
,5-diamine; [0213]
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(2-chloro-7-me-
thylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
[0214]
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(7-methylthien-
o[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine; and [0215]
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(6,7-dimethoxy-
quinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine.
[0216] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0217]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0218] R.sup.2 is a
bicyclic aryl of formula (II):
##STR00018##
[0218] where: [0219] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0220] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0221] R.sup.3 is a bicyclic aryl or a
bicyclic heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0222] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0223] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0224]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0225] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0226] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0227] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0228]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0229] R.sup.2 is a
bicyclic aryl of formula (II):
##STR00019##
[0229] where: [0230] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0231] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0232] R.sup.3 is a bicyclic heteroaryl
selected from the group consisting of benzothiazolyl, benzofuranyl,
indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl,
quinazolinyl, quinoxalinyl, imidazopyrimidinyl, pyrrolopyrimidinyl,
furopyrimidinyl, thienopyrimidinyl, thienopyridazinyl,
furopyridazinyl, pyrrolopyridazinyl, imidazopyridazinyl,
thienopyrazinyl, furopyrazinyl, pyrrolopyrazinyl and
imidazopyridinyl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, oxo, thioxo, cyano, nitro, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.1--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0233] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0234] each R.sup.18
is independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0235]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0236] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0237] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0238] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0239]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0240] R.sup.2 is a
bicyclic aryl of formula (II):
##STR00020##
[0240] where: [0241] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0242] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0243] R.sup.3 is thienopyrimidinyl optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, oxo, thioxo, cyano,
nitro, R.sup.15--OR.sup.14, R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0244] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0245] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0246]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0247] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0248] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0249] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) which is
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(9-(pyrrolidin-1-
-yl)-5,6,7,8,9,10-hexahydrobenzo[8]annulen-2-yl)-1H-1,2,4-triazole-3,5-dia-
mine.
[0250] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0251]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0252] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00021##
[0252] where: [0253] A is an alkylene chain containing six carbons
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0254] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0255] R.sup.3 is a bicyclic
heteroaryl optionally substituted by one or more substitutents
selected from the group consisting of alkyl, alkenyl, halo,
haloalkyl, oxo, thioxo, cyano, nitro, --R.sup.15--OR.sup.14,
R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0256] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0257] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0258]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0259] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0260] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0261] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0262]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0263] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00022##
[0263] where: [0264] A is an alkylene chain containing six carbons
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0265] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0266] R.sup.3 is a bicyclic
heteroaryl selected from the group consisting of benzothiazolyl,
benzofuranyl, indolyl, benzimidazolyl, indazolyl, quinolinyl,
isoquinolinyl, quinazolinyl, quinoxalinyl, imidazopyrimidinyl,
pyrrolopyrimidinyl, furopyrimidinyl, thienopyrimidinyl,
thienopyridazinyl, furopyridazinyl, pyrrolopyridazinyl,
imidazopyridazinyl, thienopyrazinyl, furopyrazinyl,
pyrrolopyrazinyl and imidazopyridinyl, each optionally substituted
by one or more substitutents selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, oxo, thioxo, cyano, nitro,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0267] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0268] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0269]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0270] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0271] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0272] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0273]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0274] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00023##
[0274] where: [0275] A is an alkylene chain containing six carbons
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0276] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0277] R.sup.3 is
thienopyrimidinyl optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, oxo, thioxo, cyano, nitro, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0278] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2;
[0279] each R.sup.8 is independently selected from the group
consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0280]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0281] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0282] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0283] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) selected from the
group consisting of: [0284]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-oxo-5,6,8,9,1-
0-pentahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0285]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrro-
lidin-1-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0286]
1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrrolidin-1-yl)-5,6,-
7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0287]
N.sup.3-(7-(cyclohexylamino)-5,6,7,8,9,10-hexahydrocycloocta[b]pyr-
idin-3-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-d-
iamine; [0288]
N.sup.3-(7-(4-methylpiperazin-1-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyr-
idin-3-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-d-
iamine.
[0289] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0290]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0291] R.sup.2 is a
bicyclic aryl or a bicyclic heteroaryl of formula (II):
##STR00024##
[0291] where: [0292] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0293] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0294] R.sup.3 is a
tricyclic aryl or a tricyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.15, --R.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0295] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0296] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0297]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0298] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0299] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0300] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0301]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0302] R.sup.2 is a
bicyclic aryl of formula (II):
##STR00025##
[0302] where: [0303] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0304] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.2 is attached; [0305] R.sup.3 is a tricyclic aryl or a
tricyclic heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, halo,
haloalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0306] each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0307] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0308]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0309] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0310] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0311] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0312]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0313] R.sup.2 is a
bicyclic heteroaryl of formula (II):
##STR00026##
[0313] where: [0314] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0315] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.2 is attached; [0316] R.sup.3 is a
tricyclic aryl or a tricyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, halo, haloalkyl, oxo, thioxo, cyano, nitro,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0317] each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0318] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0319]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0320] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0321] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0322] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0323]
R.sup.1, R.sup.4 and R.sup.5 are each independently selected from
group consisting of hydrogen, alkyl, aryl, aralkyl, --C(O)R.sup.9
and --C(O)N(R.sup.6)R.sup.7; [0324] R.sup.2 is an aryl or a
heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--C(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0325] R.sup.3 is a bicyclic aryl or a
bicyclic heteroaryl of formula (II):
##STR00027##
[0325] where: [0326] A is an alkylene chain containing six to ten
carbons, an alkenylene chain containing six to ten carbons, or an
alkynylene chain containing six to ten carbons, where one or two
carbons of the alkylene, alkenylene or alkynylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain, the
alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0327] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.3 is attached; [0328] each R.sup.6 and
R.sup.7 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0329] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0330]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; [0331] each R.sup.10 is independently selected
from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; [0332] each
R.sup.11 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain, an
optionally substituted straight or branched alkenylene chain and an
optionally substituted straight or branched alkynylene chain; and
[0333] each R.sup.12 is hydrogen, alkyl, cyano, nitro or
--OR.sup.9.
[0334] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0335]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0336] R.sup.2 is a
monocyclic aryl or a monocyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--C(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0337] R.sup.3 is a bicyclic aryl of formula
(II):
##STR00028##
[0337] where: [0338] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0339] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.3 is attached; [0340] each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0341] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0342]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0343] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0344] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0345] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0346]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0347] R.sup.2 is a
monocyclic aryl or a monocyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0348] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00029##
[0348] where: [0349] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0350] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; [0351] each R.sup.6
and R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0352] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0353]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0354] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0355] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0356] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0357]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0358] R.sup.2 is a
monocyclic aryl optionally substituted by one or more substitutents
selected from the group consisting of alkyl, alkenyl, halo,
haloalkyl, haloalkenyl, cyano, nitro, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0359] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00030##
[0359] where: [0360] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0361] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; [0362] each R.sup.6
and R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0363] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0364]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0365] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0366] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0367] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0368]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0369] R.sup.2 is
phenyl optionally substituted by one or more substitutents selected
from the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0370] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00031##
[0370] where: [0371] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.11--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0372] B.sup.1 is .dbd.N--, B.sup.2 is the carbon directly bonded
to the nitrogen to which R.sup.3 is attached, B.sup.3 is .dbd.N--
and B.sup.4 is .dbd.C(R.sup.8)--; [0373] each R.sup.6 and R.sup.7
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0374] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0375]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0376] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0377] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0378] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) selected from the
group consisting of: [0379]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N
3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0380]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(4-
-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0381]
N.sup.3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0382]
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
[0383]
N.sup.3-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
[0384]
(R)--N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,7-
,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine-
; [0385]
(S)--N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,-
7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamin-
e; [0386]
N.sup.3-(3-chloro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7-
,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine-
; [0387]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(-
4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0388]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(-
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-di-
amine; [0389]
N.sup.3-(3-fluoro-4-(4-morpholinopiperidin-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
[0390]
1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0391]
N.sup.3-(4-(4-(4-fluorophenyl)piperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexa-
hydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
[0392] ethyl
4-(4-(5-amino-1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)--
1H-1,2,4-triazol-3-ylamino)-2-fluorophenyl)piperazine-1-carboxylate;
[0393]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(2-
-methyl-2-(pyrrolidin-1-yl)propoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
and [0394]
N.sup.3-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-1-(5,6,7,8,-
9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine.
[0395] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0396]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0397] R.sup.2 is
phenyl optionally substituted by one or more substitutents selected
from the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0398] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00032##
[0398] where: [0399] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0400] B.sup.1 is .dbd.C(R.sup.3)--, B.sup.2 is the carbon directly
bonded to the nitrogen to which R.sup.3 is attached, B.sup.3 and
B.sup.4 are both .dbd.N--; [0401] each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0402] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0403]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0404] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0405] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0406] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) selected from the
group consisting of: [0407]
N.sup.3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine; [0408]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
and [0409]
1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.
[0410] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0411]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0412] R.sup.2 is
phenyl optionally substituted by one or more substitutents selected
from the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15-- OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0413] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00033##
[0413] where: [0414] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0415] B.sup.1 is the carbon directly bonded to the nitrogen to
which R.sup.3 is attached, B.sup.2 and B.sup.4 are both .dbd.N--
and B.sup.3 is .dbd.C(R.sup.8)--; [0416] each R.sup.6 and R.sup.7
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0417] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0418]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0419] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0420] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0421] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) selected from the
group consisting of: [0422]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine; and [0423]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0424]
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
[0425]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(-
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-di-
amine; and [0426]
N.sup.3-(3-fluoro-4-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)-1-(5,6,7,8,-
9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine.
[0427] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0428]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0429] R.sup.2 is
phenyl optionally substituted by one or more substitutents selected
from the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0430] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00034##
[0430] where: [0431] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0432] B.sup.1 is .dbd.N--, B.sup.2 is the carbon directly bonded
to the nitrogen to which R.sup.3 is attached, and B.sup.3 and
B.sup.4 are both .dbd.C(R.sup.8)--; [0433] each R.sup.6 and R.sup.7
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0434] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0435]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0436] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0437] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0438] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) selected from the
group consisting of: [0439]
1-(5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(4-methylpi-
perazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0440]
1-(5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(2-(pyrroli-
din-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0441]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(4-pheny-
l-5,6,7,8,9,10-hexahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-d-
iamine; [0442]
N.sup.3-(4-(4-methylpiperazin-1-yl)phenyl)-1-(4-phenyl-5,6,7,8,9,10-Hexah-
ydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine; and
[0443]
N.sup.3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(4-phenyl-5,6,7,8,9,10-he-
xahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine.
[0444] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0445]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0446] R.sup.2 is a
monocyclic heteroaryl optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0447] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00035##
[0447] where: [0448] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0449] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; [0450] each R.sup.6
and R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0451] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0452]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0453] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0454] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0455] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0456]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0457] R.sup.2 is
pyridinyl optionally substituted by one or more substitutents
selected from the group consisting of alkyl, alkenyl, halo,
haloalkyl, haloalkenyl, cyano, nitro, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0458] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00036##
[0458] where: [0459] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0460] B.sup.1 is the carbon directly bonded to the nitrogen to
which R.sup.3 is attached, B.sup.2 and B.sup.4 are both .dbd.N--
and B.sup.3 is .dbd.C(R.sup.8)--; [0461] each R.sup.6 and R.sup.7
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0462] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0463]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0464] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0465] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0466] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) selected from the
group consisting of: [0467]
N.sup.3-(6-(4-(azepan-1-yl)piperidin-1-yl)pyridin-3-yl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;
and [0468]
N.sup.3-(6-(4-((pyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl-
)-1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3-
,5-diamine.
[0469] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0470]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0471] R.sup.2 is a
bicyclic aryl or a bicyclic heteroaryl, each optionally substituted
by one or more substitutents selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0472] R.sup.3 is a bicyclic aryl or a
bicyclic heteroaryl of formula (II):
##STR00037##
[0472] where: [0473] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0474] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.3 is attached; [0475] each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0476] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0477]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0478] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0479] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0480] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0481]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0482] R.sup.2 is a
bicyclic aryl or a bicyclic heteroaryl, each optionally substituted
by one or more substitutents selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0483] R.sup.3 is a bicyclic aryl of formula
(II):
##STR00038##
[0483] where: [0484] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--C(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0485] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.3 is attached; [0486] each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0487] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0488]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0489] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0490] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0491] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0492]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0493] R.sup.2 is a
bicyclic aryl or a bicyclic heteroaryl, each optionally substituted
by one or more substitutents selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0494] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00039##
[0494] where: [0495] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0496] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; [0497] each R.sup.6
and R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0498] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0499]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0500] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0501] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0502] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0503]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0504] R.sup.2 is a
bicyclic heteroaryl selected from the group consisting of
benzothiazolyl, benzofuranyl, indolyl, benzimidazolyl, indazolyl,
quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,
imidazopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl,
thienopyrimidinyl, thienopyridazinyl, furopyridazinyl,
pyrrolopyridazinyl, imidazopyridazinyl, thienopyrazinyl,
furopyrazinyl, pyrrolopyrazinyl and imidazopyridinyl, each
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, alkenyl, halo, haloalkyl, oxo,
thioxo, cyano, nitro, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0505] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00040##
[0505] where: [0506] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0507] B.sup.1 is .dbd.N--, B.sup.2 is the carbon directly bonded
to the nitrogen to which R.sup.3 is attached, B.sup.3 is .dbd.N--
and B.sup.4 is .dbd.C(R.sup.8)--; [0508] each R.sup.6 and R.sup.7
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0509] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0510]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0511] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0512] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0513] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) which is
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(2-methyl-1,-
2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine.
[0514] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0515]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0516] R.sup.2 is a
tricyclic aryl or a tricyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--C(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0517] R.sup.3 is a bicyclic aryl or a
bicyclic heteroaryl of formula (II):
##STR00041##
[0517] where: [0518] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0519] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which R.sup.3 is attached; [0520] each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0521] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0522]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0523] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0524] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0525] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0526]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0527] R.sup.2 is a
tricyclic aryl or a tricyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0528] R.sup.3 is a bicyclic aryl of formula
(II):
##STR00042##
[0528] where: [0529] A is an alkylene chain containing six carbons,
where each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0530] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)--, provided that one of B.sup.1, B.sup.2, B.sup.3
and B.sup.4 is a carbon directly bonded to the nitrogen to which
R.sup.3 is attached; [0531] each R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0532] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.11--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0533]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0534] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0535] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0536] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0537]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0538] R.sup.2 is a
tricyclic aryl or a tricyclic heteroaryl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.15--OR.sup.14, --R.sup.15--OC(O)--R.sup.14,
--R.sup.15--N(R.sup.14).sub.2, --R.sup.15--C(O)R.sup.14,
--R.sup.15--C(O)OR.sup.14, --R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0539] R.sup.3 is a bicyclic heteroaryl of
formula (II):
##STR00043##
[0539] where: [0540] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0541] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which R.sup.3 is attached; [0542] each R.sup.6
and R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0543] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0544]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0545] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0546] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0547] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0548]
R.sup.1, R.sup.4 and R.sup.5 are each independently selected from
group consisting of hydrogen, alkyl, aryl, aralkyl, --C(O)R.sup.9
and --C(O)N(R.sup.6)R.sup.7; [0549] R.sup.2 and R.sup.3 are each
independently a bicyclic aryl or a bicyclic heteroaryl of formula
(I):
##STR00044##
[0549] where: [0550] A is an alkylene chain containing six to ten
carbons, an alkenylene chain containing six to ten carbons, or an
alkynylene chain containing six to ten carbons, where one or two
carbons of the alkylene, alkenylene or alkynylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain, the
alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10, --R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0551] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
[0552] each R.sup.6 and R.sup.7 is independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aralkenyl, optionally substituted aralkynyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.11--OR.sup.9,
--R.sup.11--CN, --R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0553] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0554]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; [0555] each R.sup.10 is independently selected
from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; [0556] each
R.sup.11 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain, an
optionally substituted straight or branched alkenylene chain and an
optionally substituted straight or branched alkynylene chain; and
[0557] each R.sup.12 is hydrogen, alkyl, cyano, nitro or
--OR.sup.9.
[0558] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0559]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0560] R.sup.2 and
R.sup.3 are each a bicyclic aryl of formula (II):
##STR00045##
[0560] where: [0561] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0562] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
[0563] each R.sup.6 and R.sup.7 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.11--OR.sup.9,
--R.sup.11--CN, --R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0564] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0565]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0566] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0567] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0568] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0569]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0570] R.sup.2 and
R.sup.3 are each a bicyclic heteroaryl of formula (II):
##STR00046##
[0570] where: [0571] A is an alkylene chain containing six carbons,
where one or two carbons of the alkylene chain is optionally
replaced by --NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p
is 0, 1 or 2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where
each carbon in the alkylene chain is independently optionally
substituted by one or two substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0572] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that at least one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is .dbd.N-- and that one of
B.sup.1, B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded
to the nitrogen to which its corresponding R.sup.2 or R.sup.3 is
attached; [0573] each R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.11--OR.sup.9, --R.sup.11--CN, --R.sup.11--NO.sub.2,
--R.sup.11--N(R.sup.9).sub.2, --R.sup.11--C(O)OR.sup.9 and
--R.sup.11--C(O)N(R.sup.9).sub.2, or any R.sup.6 and R.sup.7,
together with the common nitrogen to which they are both attached,
form an optionally substituted N-heteroaryl or an optionally
substituted N-heterocyclyl; [0574] each R.sup.8 is independently
selected from the group consisting of hydrogen, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0575]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0576] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0577] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0578] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0579]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0580] R.sup.2 is a
bicyclic aryl of formula (II) having the following formula
(IIa):
##STR00047##
[0580] where: [0581] Aa is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0582] B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a are each
independently .dbd.C(R.sup.8)--, provided that one of B.sup.1a,
B.sup.2a, B.sup.3a and B.sup.4a is a carbon directly bonded to the
nitrogen to which R.sup.2 is attached; [0583] R.sup.3 is a bicyclic
heteroaryl of formula (II) having the following formula (IIb):
##STR00048##
[0583] where: [0584] Ab is an alkylene chain containing six
carbons, where each carbon of the alkylene chain may be replaced by
--NR.sup.9--, .dbd.N--, --O--, --S(O).sub.p-- (where p is 0, 1 or
2) or --P(O).sub.p-- (where p is 0, 1 or 2) and where each carbon
in the alkylene chain is independently optionally substituted by
one or two substituents selected from the group consisting of oxo,
thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl,
cycloalkylalkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0585] B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b are each
independently .dbd.C(R.sup.8)-- or .dbd.N--, provided that at least
one of B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b is .dbd.N-- and
one of B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b is a carbon
directly bonded to the nitrogen to which R.sup.3 is attached;
[0586] each R.sup.6 and R.sup.7 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.11--OR.sup.9,
--R.sup.11--CN, --R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0587] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0588]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0589] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0590] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0591] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein: [0592]
R.sup.1, R.sup.4 and R.sup.5 are each hydrogen; [0593] R.sup.2 is a
bicyclic heteroaryl of formula (II) having the following formula
(IIa):
##STR00049##
[0593] where: [0594] Aa is an alkylene chain containing six
carbons, where one or two carbons of the alkylene chain is
optionally replaced by --NR.sup.9--, .dbd.N--, --O--,
--S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p-- (where p is
0, 1 or 2) and where each carbon in the alkylene chain is
independently optionally substituted by one or two substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0595] B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a are each
independently .dbd.C(R.sup.8)-- or .dbd.N--, provided that at least
one of B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a is .dbd.N-- and
that one of B.sup.1a, B.sup.2a, B.sup.3a and B.sup.4a is a carbon
directly bonded to the nitrogen to which R.sup.2 is attached;
[0596] R.sup.3 is a bicyclic aryl of formula (II) having the
following formula (IIb):
##STR00050##
[0596] where: [0597] Ab is an alkylene chain containing six
carbons, where each carbon in the alkylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl,
--R.sup.10--OR.sup.9, --R.sup.10--OC(O)--R.sup.9,
--R.sup.10--N(R.sup.6)R.sup.7, --R.sup.10--C(O)R.sup.9,
--R.sup.10--C(O)OR.sup.9, --R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0598] B.sup.1b, B.sup.2b, B.sup.3b and B.sup.4b are each
independently .dbd.C(R.sup.8)--, provided that one of B.sup.1b,
B.sup.2b, B.sup.3b and B.sup.4b is a carbon directly bonded to the
nitrogen to which R.sup.3 is attached; [0599] each R.sup.6 and
R.sup.7 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0600] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0601]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, and
optionally substituted heteroarylalkyl; [0602] each R.sup.10 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0603] each R.sup.11 is an optionally substituted straight or
branched alkylene chain.
[0604] Another embodiment of a compound of formula (Ia), as set
forth above, is the compound of formula (Ia) wherein:
##STR00051##
wherein: [0605] R.sup.1, R.sup.4 and R.sup.5 are each independently
selected from group consisting of hydrogen, alkyl, aryl, aralkyl,
--C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7; [0606] R.sup.2 and
R.sup.3 are each independently a bicyclic aryl or a bicyclic
heteroaryl of formula (II):
[0606] ##STR00052## [0607] where: [0608] A is an alkylene chain
containing six to ten carbons, an alkenylene chain containing six
to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--OR.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0609] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
[0610] or R.sup.2 is selected from the group consisting of a
bicyclic aryl and a bicyclic heteroaryl of formula (II), as defined
above, and R.sup.3 is selected from the group consisting of aryl
and heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0611] or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; [0612] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0613] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0614]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; [0615] each R.sup.10 is independently selected
from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; [0616] each
R.sup.11 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain, an
optionally substituted straight or branched alkenylene chain and an
optionally substituted straight or branched alkynylene chain; and
[0617] each R.sup.12 is hydrogen, alkyl, cyano, nitro or
--OR.sup.9; as an isolated stereoisomer or a mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0618] Another embodiment of the invention, as set forth above in
the Summary of the Invention, is where the compound of formula (I)
is a compound of formula (Ib):
##STR00053##
wherein: [0619] R.sup.1, R.sup.4 and R.sup.5 are each independently
selected from group consisting of hydrogen, alkyl, aryl, aralkyl,
--C(O)R.sup.9 and --C(O)N(R.sup.6)R.sup.7; [0620] R.sup.2 and
R.sup.3 are each independently a bicyclic aryl or a bicyclic
heteroaryl of formula (II):
[0620] ##STR00054## [0621] where: [0622] A is an alkylene chain
containing six to ten carbons, an alkenylene chain containing six
to ten carbons, or an alkynylene chain containing six to ten
carbons, where one or two carbons of the alkylene, alkenylene or
alkynylene chain is optionally replaced by --NR.sup.9--, .dbd.N--,
--O--, --S(O).sub.p-- (where p is 0, 1 or 2) or --P(O).sub.p--
(where p is 0, 1 or 2) and where each carbon in the alkylene chain,
the alkenylene chain or the alkynylene chain is independently
optionally substituted by one or two substituents selected from the
group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
--R.sup.10--OR.sup.9, --R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0623] B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently
.dbd.C(R.sup.8)-- or .dbd.N--, provided that one of B.sup.1,
B.sup.2, B.sup.3 and B.sup.4 is a carbon directly bonded to the
nitrogen to which its corresponding R.sup.2 or R.sup.3 is attached;
[0624] or R.sup.2 is selected from the group consisting of a
bicyclic aryl and a bicyclic heteroaryl of formula (II), as defined
above, and R.sup.3 is selected from the group consisting of aryl
and heteroaryl, each optionally substituted by one or more
substitutents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,
cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain; [0625] or R.sup.2 is selected from the group
consisting of aryl and heteroaryl, each optionally substituted by
one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.15--OR.sup.14,
--R.sup.15--OC(O)--R.sup.14, --R.sup.15--N(R.sup.14).sub.2,
--R.sup.15--C(O)R.sup.14, --R.sup.15--C(O)OR.sup.14,
--R.sup.15--C(O)N(R.sup.14).sub.2,
--R.sup.15--N(R.sup.14)C(O)OR.sup.14,
--R.sup.15--N(R.sup.14)C(O)R.sup.14,
--R.sup.15--N(R.sup.14)S(O).sub.tR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.tOR.sup.14 (where t is 1 or 2),
--R.sup.15--S(O).sub.pR.sup.14 (where p is 0, 1 or 2), and
--R.sup.15--S(O).sub.tN(R.sup.14).sub.2 (where t is 1 or 2), where
each R.sup.14 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R.sup.15
is independently a direct bond or a straight or branched alkylene
or alkenylene chain, and R.sup.3 is selected from the group
consisting of a bicyclic aryl and a bicyclic heteroaryl of formula
(II), as defined above; [0626] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.11--OR.sup.9, --R.sup.11--CN,
--R.sup.11--NO.sub.2, --R.sup.11--N(R.sup.9).sub.2,
--R.sup.11--C(O)OR.sup.9 and --R.sup.11--C(O)N(R.sup.9).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0627] each R.sup.8 is
independently selected from the group consisting of hydrogen,
cyano, nitro, halo, haloalkyl, alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, --R.sup.10--OR.sup.9,
--R.sup.10--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--O--R.sup.11--OR.sup.9,
--R.sup.10--O--R.sup.11--CN, --R.sup.10--O--R.sup.11--C(O)OR.sup.9,
--R.sup.10--O--R.sup.11--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--S(O).sub.pR.sup.9 (where p is 0, 1 or 2),
--R.sup.10--O--R.sup.11--N(R.sup.6)R.sup.7,
--R.sup.10--O--R.sup.11--C(NR.sup.12)N(R.sup.12)H,
--R.sup.10--OC(O)--R.sup.9, --R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.10--C(O)R.sup.9, --R.sup.10--C(O)OR.sup.9,
--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.10--N(R.sup.6)C(O)OR.sup.14,
--R.sup.10--N(R.sup.6)C(O)R.sup.9,
--R.sup.10--N(R.sup.6)S(O).sub.tR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.tOR.sup.9 (where t is 1 or 2),
--R.sup.10--S(O).sub.pR.sup.9 (where p is 0, 1 or 2), and
--R.sup.10--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0628]
each R.sup.9 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkynyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, and optionally substituted
heteroarylalkynyl; [0629] each R.sup.10 is independently selected
from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain and an optionally
substituted straight or branched alkynylene chain; [0630] each
R.sup.11 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain, an
optionally substituted straight or branched alkenylene chain and an
optionally substituted straight or branched alkynylene chain; and
[0631] each R.sup.12 is hydrogen, alkyl, cyano, nitro or
--OR.sup.9; as an isolated stereoisomer or a mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0632] Preferred embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 of the compounds of formula (Ib) are the same as set
forth above for R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 of
the compounds of formula (Ia).
[0633] In any of the embodiments disclosed above, preferred
optionally substituted tricyclic heteroaryls for R.sup.2 or R.sup.3
are selected from the group consisting of benzonaphthofuranyl,
benzothieno[3,2-d]pyrimidinyl, benzo[4,6]imidazo[1,2-a]pyridinyl,
carbazolyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, phenanthridinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, and
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl.
[0634] In any of the embodiments disclosed above, preferred
optionally substituted bicyclic heteroaryls for R.sup.2 or R.sup.3
are selected from the group consisting of benzothiazolyl,
benzofuranyl, indolyl, benzimidazolyl, indazolyl, quinolinyl,
isoquinolinyl, quinazolinyl, quinoxalinyl, imidazopyrimidinyl,
pyrrolopyrimidinyl, furopyrimidinyl, thienopyrimidinyl,
thienopyridazinyl, furopyridazinyl, pyrrolopyridazinyl,
imidazopyridazinyl, thienopyrazinyl, furopyrazinyl,
pyrrolopyrazinyl and imidazopyridinyl.
[0635] In any of the embodiments disclosed above, preferred
optionally substituted monocyclic heteroaryls for R.sup.2 and
R.sup.3 are selected from the group consisting of furanyl, thienyl,
pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
[0636] Of the various aspects of the pharmaceutical compositions of
the invention comprising a pharmaceutically acceptable excipient
and a compound of formula (I), as set forth above in the Summary of
the Invention, certain embodiments are preferred.
[0637] One embodiment of these pharmaceutical compositions is
wherein the compound of formula (I) therein is selected from any
one embodiment of the compound of formula (Ia), as set forth above,
or from any combination of embodiments of the compound of formula
(Ia), as set forth above, or the compound of formula (I) therein is
selected from any one embodiment of the compound of formula (Ib),
as set forth above, or from any combination of embodiments of the
compound of formula (Ib), as set forth above.
[0638] Of the various aspects of methods of treating a disease or
condition associated with Axl activity in a mammal, wherein the
method comprises administering to a mammal in need thereof a
therapeutically effective amount of a compound of formula (I),
certain embodiments are preferred.
[0639] One embodiment of these methods is the method wherein the
disease or condition is selected from the group consisting of
rheumatoid arthritis, vascular disease, vascular injury, psoriasis,
visual impairment due to macular degeneration, diabetic
retinopathy, retinopathy of prematurity, kidney disease,
osteoporosis, osteoarthritis and cataracts.
[0640] One embodiment of these methods is the method wherein a
manifestation of the disease or condition is solid tumor formation
in said mammal.
[0641] One embodiment of these methods is the method wherein the
disease or condition is selected from the group consisting of
breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian
carcinoma, thyroid carcinoma, non-small cell lung carcinoma, and
uveal melanoma.
[0642] One embodiment of these methods is the method wherein a
manifestation of the disease or condition is liquid tumor formation
in said mammal.
[0643] One embodiment of these methods is the method wherein the
disease or condition is myeloid leukemia or lymphoma.
[0644] One embodiment of these methods is the method wherein the
disease or condition is endometriosis.
[0645] One embodiment of these methods is the method wherein the
compounds of formula (I) utilized therein is selected from any one
embodiment of the compound of formula (Ia), as set forth above, or
from any combination of embodiments of the compound of formula
(Ia), as set forth above, or the compound of formula (I) therein is
selected from any one embodiment of the compound of formula (Ib),
as set forth above, or from any combination of embodiments of the
compound of formula (Ib), as set forth above.
[0646] Another embodiment of the invention are those methods of
treating a disease or condition associated with Axl activity by
administering to the mammal a therapeutically effective amount of a
pharmaceutical composition of the invention, as set forth above in
the Summary of the Invention, wherein the disease or condition is
selected from the group consisting of rheumatoid arthritis,
vascular disease/injury (including but not limited to restenosis,
atherosclerosis and thrombosis), psoriasis, visual impairment due
to macular degeneration, diabetic retinopathy or retinopathy of
prematurity, kidney disease (including but not limited to
glomerulonephritis, diabetic nephropathy and renal transplant
rejection), osteoporosis, osteoarthritis and cataracts.
[0647] Another embodiment of the invention are those methods of
treating a disease or condition associated with Axl activity by
administering to the mammal a therapeutically effective amount of a
pharmaceutical composition of the invention, as set forth above in
the Summary of the Invention, wherein the disease or condition is
selected from the group consisting of breast carcinoma, renal
carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid
carcinoma, non-small cell lung carcinoma, melanoma, prostate
carcinoma, sarcoma, gastric cancer, uveal melanoma, myeloid
leukemia and lymphoma.
[0648] Another embodiment of the invention are those methods of
treating a disease or condition associated with Axl activity by
administering to the mammal of therapeutically effective amount of
a pharmaceutical composition of the invention, as set forth above
in the Summary of the Invention, wherein the disease or condition
is endometriosis.
[0649] It is understood that any embodiment of the compounds of
formula (Ia) and compounds of formula (Ib), as set forth above, and
any specific substituent set forth herein for a R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.14 and R.sup.15 group in the
compounds of formula (Ia) and the compounds of formula (Ib), as set
forth above, may be independently combined with other embodiments
and/or substituents of compounds of formula (Ia) and compounds of
formula (Ib) to form embodiments of the inventions not specifically
set forth above. In addition, in the event that a list of
substitutents is listed for any particular R group in a particular
embodiment and/or claim, it is understood that each individual
substituent may be deleted from the particular embodiment and/or
claim and that the remaining list of substituents will be
considered to be within the scope of the invention.
[0650] Specific embodiments of the invention are described in more
detail in the following sections.
Utility and Testing of the Compounds of the Invention
[0651] The oncogenic RTK, Axl, was recently identified, using a
retroviral-based functional genetic screening protocol, as a
regulator of haptotactic migration, which is a key event in
angiogenesis. Axl inhibition by RNAi-mediated silencing blocked
endothelial cell migration, proliferation and in vitro tube
formation. These observations, which were disclosed at the American
Association Cancer Research General Meeting, Apr. 16-20, 2005,
Anaheim, Calif., and The 7th Annual Symposium on Anti-Angiogenic
Agents, Feb. 10-13, 2005, San Diego, Calif.; (Requirement for The
Receptor Tyrosine Kinase Axl in Angiogenesis and Tumor Growth,
Holland, S. J. Powell, M. J., Franci, C., Chan, E., Friera, A. M.,
Atchison, R., Xu, W., McLaughlin, J., Swift, S. E., Pali, E., Yam,
G., Wong, S., Xu, X., Hu, Y., Lasaga, J., Shen, M., Yu, S., Daniel,
R., Hitoshi, Y., Bogenberger, J., Nor, J. E., Payan, D. G and
Lorens, J. B), were substantiated by an in vivo study which
demonstrated that stable, shRNAi-mediated Axl knockdown impaired
formation of functional human blood vessels in a mouse model of
human angiogenesis. These observations were published in a peer
reviewed journal (Holland S J, Powell M J, Franci C, Chan E W,
Friera A M, Atchison R E, McLaughlin J, Swift S E, Pali E S, Yam G,
Wong S, Lasaga J, Shen M R, Yu S, Xu W, Hitoshi Y, Bogenberger J,
Nor J E, Payan D G, Lorens J B. "Multiple roles for the receptor
tyrosine kinase axl in tumor formation." Cancer Res. (2005) Vol 65
pp 9294-303. These observations are also disclosed in U.S.
Published Patent Application 2005/0118604 and European Patent
Application 1 563 094, the disclosures of which are incorporated in
full by reference. Axl signaling, therefore, impacts multiple
functions required for neovascularization in vitro, and regulates
angiogenesis in vivo. Regulation of these pro-angiogenic processes
required the catalytic activity of Axl. Thus, Axl-mediated
angiogenic stimulation would be amenable to modulation by a small
molecule inhibitor of Axl catalytic activity.
[0652] Accordingly, the compounds of the invention are small
molecule inhibitors of Axl catalytic activity, and are therefore
useful in treating diseases and conditions which are associated
with Axl catalytic activity including those diseases and conditions
which are characterized by angiogenesis and/or cell proliferation.
In particular, the compounds of the invention and pharmaceutical
compositions of the invention are useful in treating diseases and
conditions which are alleviated by the modulation of Axl activity.
For purposes of this invention, diseases and conditions which are
alleviated by the "modulation of Axl activity" includes diseases
and conditions which are alleviated by a decrease in Axl activity
and diseases and conditions which are alleviated by an increase in
Axl activity. Preferably such diseases and conditions are
alleviated by a decrease in Axl activity. Diseases and conditions
which are alleviated by the modulation of Axl activity include, but
are not limited to, solid tumors, including, but not limited to,
breast, renal, endometrial, ovarian, thyroid, and non-small cell
lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric
cancer and uveal melanoma; liquid tumors, including but not limited
to, leukemias (particularly myeloid leukemias) and lymphomas;
endometriosis, vascular disease/injury (including but not limited
to restenosis, atherosclerosis and thrombosis), psoriasis; visual
impairment due to macular degeneration; diabetic retinopathy and
retinopathy of prematurity; kidney disease (including but not
limited to glomerulonephritis, diabetic nephropathy and renal
transplant rejection), rheumatoid arthritis; osteoarthritis,
osteoporosis and cataracts.
[0653] In addition to the foregoing, the compounds of the invention
are useful in treating diseases and conditions which are affected
by the following biological processes: Invasion, migration,
metastasis, or drug resistance as manifested in cancer; stem cell
biology as manifested in cancer; invasion, migration, adhesion, or
angiogenesis as manifested in endometriosis; vascular remodeling as
manifested in cardiovascular disease, hypertension or vascular
injury; bone homeostatasis as manifested in osteoporosis or
osteoarthritis; viral infection as manifested, for example, in
ebola virus infection; or differentiation as manifested in obesity.
The compounds of the invention may also be used to modulate
inflammatory processes by treating sepsis, acting as vaccine
adjuvants, and/or potentiating the immune response in
immuno-compromised patients.
[0654] The following animal models provide guidance to one of
ordinary skill in the art in testing the compounds of the invention
for their use in treating the disease or condition indicated.
[0655] The compounds of the invention may be tested for their use
in treating leukemias and lymphomas by testing the compounds in the
xenograft in SCID mouse model using human Axl-expresing cancer cell
lines including, but not limited to, HeLa, MDA-MB-231, SK-OV-3,
OVCAR-8, DU145, H1299, ACHN, A498 and Caki-1.
[0656] The compounds of the invention may be tested for their use
in treating leukemias in the xenograft in SCID or nu/nu mouse model
using human Axl-expressing AML and CML leukemia cell lines.
[0657] The compounds of the invention may be tested for their use
in treating endometriosis by using the syngenic mouse model of
endometriosis (see Somigliana, E. et al., "Endometrial ability to
implant in ectopic sites can be prevented by interleukin-12 in a
murine model of endometriosis", Hum. Reprod. (1999), Vol. 14, NO.
12, pp. 2944-50). The compounds may also be tested for their use in
treating endometriosis by using the rat model of endometriosis (see
Lebovic, D. I. et al., "Peroxisome proliferator-activated
receptor-gamma induces regression of endometrial explants in a rat
model of endometriosis", Fertil. Steril. (2004), 82 Suppl 3, pp.
1008-13).
[0658] The compounds of the invention may be tested for their use
in treating restenosis by using the balloon-injured rate carotid
artery model (see Kim, D. W. et al., "Novel oral formulation of
paclitaxel inhibits neointimal hyperplasia in a rat carotid artery
injury model", Circulation (2004), Vol. 109, No. 12, pp. 1558-63,
Epub 2004 Mar. 8).
[0659] The compounds of the invention may also be tested for their
use in treating restenosis by using the percutaneous transluminal
coronary angioplasty in apoE deficient mouse model (see von der
Thusen, J. H. et al., "Adenoviral transfer of endothelial nitric
oxide synthase attenuates lesion formation in a novel murine model
of postangioplasty restenosis", Arterioscler, Thromb. Vasc. Biol.
(2004), Vol. 24, No. 2, pp. 357-62).
[0660] The compounds of the invention may be tested for their use
in treating atherosclerosis/thrombosis in the ApoE deficient mouse
model (see Nakashima, Y. et al., "ApoE-deficient mice develop
lesions of all phases of atherosclerosis throughout the arterial
tree", Arterioscler. Thromb. (1994), Vol. 14, No. 1, pp.
133-40).
[0661] The compounds of the invention may also be tested for their
use in treating thrombosis using the collagen-epinephrin-induced
pulmonary thromboembolism model and the stasis induced venous
thrombosis model (see Angelillo-Scherrer A. et al., "Role of Gas6
receptors in platelet signaling during thrombus stabilization and
implications for antithrombotic therapy", J Clin Invest. (2005) Vol
115 pp 237-46).
[0662] The compounds of the invention may be tested for their use
in treating psoriasis by using the SCID mouse model or the human
skin model of psoriasis (see Nickoloff, B. J. et al., "Severe
combined immunodeficiency mouse and human psoriatic skin chimeras.
Validation of a new animal model", Am. J. Pathol. (1995), Vol. 146,
No. 3, pp. 580-8).
[0663] The compounds of the invention may be tested for their use
in treating age-related macular degeneration or diabetic
retinopathy by using the rat corneal angiogenesis model (see
Sarayba M A, Li L, Tungsiripat T, Liu N H, Sweet P M, Patel A J,
Osann K E, Chittiboyina A, Benson S C, Pershadsingh H A, Chuck R S.
Inhibition of corneal neovascularization by a peroxisome
proliferator-activated receptor-gamma ligand. Exp Eye Res. 2005
March; 80(3):435-42) or the laser-induced mouse choroidal
neovasculation model (see Bora, P. S., et al., "Immunotherapy for
choroidal neovascularization in a laser-induced mouse model
simulating exudative (wet) macular degeneration", Proc. Natl. Acad.
Sci. U.S.A. (2003), Vol. 100, No. 5, pp. 2679-84, Epub 2003 Feb.
14).
[0664] The compounds of the invention may be tested for their use
in treating retinopathy of prematurity in the mouse retinopathy of
prematurity model (see Smith, L. E. et al., "Oxygen-induced
retinopathy in the mouse", Invest. Opthalmol. Vis. Sci. (1994),
Vol. 35, No. 1, pp. 101-11).
[0665] The compounds of the invention may be tested for their use
in treating glomerulonephritis or diabetic nephropathy in the rat
anti-Thy1.1-induced experimental mesangial proliferative
glomerulonephritis model (see Smith, L. E. et al. cited above).
[0666] The compounds of the invention may be tested for their use
in treating renal tranplant rejection by using a rat model of
chronic renal transplant rejection (see Yin, J. L. et al.,
"Expression of growth arrest-specific gene 6 and its receptors in a
rat model of chronic renal transplant rejection", Transplantation
(2002), Vol. 73, No. 4, pp. 657-60).
[0667] The compounds of the invention may be tested for their use
in treating rheumatoid arthritis by using the CAIA mouse model (see
Phadke, K. et al., "Evaluation of the effects of various
anti-arthritic drugs on type II collagen-induced mouse arthritis
model", Immunopharmacology (1985) Vol. 10, No. 1, pp. 51-60).
[0668] The compounds of the invention may be tested for their use
in treating osteoarthritis by using the STR/ORT mouse model (see
Brewster, M. et al., "Ro 32-3555, an orally active collagenase
selective inhibitor, prevents structural damage in the STR/ORT
mouse model of osteoarthritis", Arthritis. Rheum. (1998), Vol. 41,
No. 9, pp. 1639-44).
[0669] The compounds of the invention may be tested for their use
in treating osteoporosis by using the ovariectomized rat model (see
Wronski, T. J. et al., "Endocrine and pharmacological suppressors
of bone turnover protect against osteopenia in ovariectomized
rats", Endocrinology (1989), Vol. 125, no. 2, pp 810-6) or the
ovariectomized mouse model (see Alexander, J. M. et al., "Human
parathyroid hormone 1-34 reverses bone loss in ovariectomized
mice", J Bone Miner Res. (2001), Vol. 16, no. 9, pp 1665-73;
Fujioka, M. et al., "Equol, a metabolite of daidzein, inhibits bone
loss in ovariectomized mice", J Nutr. (2004), Vol. 134, no. 10, pp
2623-7).
[0670] The compounds of the invention may be tested for their use
in treating cataracts by using the H.sub.2O.sub.2-induced model
(see Kadoya, K. et al., "Role of calpain in hydrogen peroxide
induced cataract", Curr. Eye Res. (1993), Vol. 12, No. 4, pp.
341-6) or the Emory mouse model (see Sheets, N. L. et al.,
"Cataract- and lens-specific upregulation of ARK receptor tyrosine
kinase in Emory mouse cataract", Invest Opthalmol. Vis. Sci.
(2002), Vol. 43, No. 6, pp. 1870-5).
Pharmaceutical Compositions of the Invention and Administration
[0671] Administration of the compounds of the invention, or their
pharmaceutically acceptable salts, in pure form or in an
appropriate pharmaceutical composition, can be carried out via any
of the accepted modes of administration of agents for serving
similar utilities. The pharmaceutical compositions of the invention
can be prepared by combining a compound of the invention with an
appropriate pharmaceutically acceptable carrier, diluent or
excipient, and may be formulated into preparations in solid,
semi-solid, liquid or gaseous forms, such as tablets, capsules,
powders, granules, ointments, solutions, suppositories, injections,
inhalants, gels, microspheres, and aerosols. Typical routes of
administering such pharmaceutical compositions include, without
limitation, oral, topical, transdermal, inhalation, parenteral,
sublingual, buccal, rectal, vaginal, and intranasal. The term
parenteral as used herein includes subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques. Pharmaceutical compositions of the invention are
formulated so as to allow the active ingredients contained therein
to be bioavailable upon administration of the composition to a
patient. Compositions that will be administered to a subject or
patient take the form of one or more dosage units, where for
example, a tablet may be a single dosage unit, and a container of a
compound of the invention in aerosol form may hold a plurality of
dosage units. Actual methods of preparing such dosage forms are
known, or will be apparent, to those skilled in this art; for
example, see Remington: The Science and Practice of Pharmacy, 20th
Edition (Philadelphia College of Pharmacy and Science, 2000). The
composition to be administered will, in any event, contain a
therapeutically effective amount of a compound of the invention, or
a pharmaceutically acceptable salt thereof, for treatment of a
disease or condition of interest in accordance with the teachings
of this invention.
[0672] A pharmaceutical composition of the invention may be in the
form of a solid or liquid. In one aspect, the carrier(s) are
particulate, so that the compositions are, for example, in tablet
or powder form. The carrier(s) may be liquid, with the compositions
being, for example, an oral oil, injectable liquid or an aerosol,
which is useful in, for example, inhalatory administration.
[0673] When intended for oral administration, the pharmaceutical
composition is preferably in either solid or liquid form, where
semi-solid, semi-liquid, suspension and gel forms are included
within the forms considered herein as either solid or liquid.
[0674] As a solid composition for oral administration, the
pharmaceutical composition may be formulated into a powder,
granule, compressed tablet, pill, capsule, chewing gum, wafer or
the like form. Such a solid composition will typically contain one
or more inert diluents or edible carriers. In addition, one or more
of the following may be present: binders such as
carboxymethylcellulose, ethyl cellulose, microcrystalline
cellulose, gum tragacanth or gelatin; excipients such as starch,
lactose or dextrins, disintegrating agents such as alginic acid,
sodium alginate, Primogel, corn starch and the like; lubricants
such as magnesium stearate or Sterotex; glidants such as colloidal
silicon dioxide; sweetening agents such as sucrose or saccharin; a
flavoring agent such as peppermint, methyl salicylate or orange
flavoring; and a coloring agent.
[0675] When the pharmaceutical composition is in the form of a
capsule, for example, a gelatin capsule, it may contain, in
addition to materials of the above type, a liquid carrier such as
polyethylene glycol or oil.
[0676] The pharmaceutical composition may be in the form of a
liquid, for example, an elixir, syrup, solution, emulsion or
suspension. The liquid may be for oral administration or for
delivery by injection, as two examples. When intended for oral
administration, preferred composition contain, in addition to the
present compounds, one or more of a sweetening agent,
preservatives, dye/colorant and flavor enhancer. In a composition
intended to be administered by injection, one or more of a
surfactant, preservative, wetting agent, dispersing agent,
suspending agent, buffer, stabilizer and isotonic agent may be
included.
[0677] The liquid pharmaceutical compositions of the invention,
whether they be solutions, suspensions or other like form, may
include one or more of the following adjuvants: sterile diluents
such as water for injection, saline solution, preferably
physiological saline, Ringer's solution, isotonic sodium chloride,
fixed oils such as synthetic mono or diglycerides which may serve
as the solvent or suspending medium, polyethylene glycols,
glycerin, propylene glycol or other solvents; antibacterial agents
such as benzyl alcohol or methyl paraben; antioxidants such as
ascorbic acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The parenteral preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic. Physiological saline is a preferred
adjuvant. An injectable pharmaceutical composition is preferably
sterile.
[0678] A liquid pharmaceutical composition of the invention
intended for either parenteral or oral administration should
contain an amount of a compound of the invention such that a
suitable dosage will be obtained. Typically, this amount is at
least 0.01% of a compound of the invention in the composition. When
intended for oral administration, this amount may be varied to be
between 0.1 and about 70% of the weight of the composition.
Preferred oral pharmaceutical compositions contain between about 4%
and about 75% of the compound of the invention. Preferred
pharmaceutical compositions and preparations according to the
present invention are prepared so that a parenteral dosage unit
contains between 0.01 to 10% by weight of the compound prior to
dilution of the invention.
[0679] The pharmaceutical composition of the invention may be
intended for topical administration, in which case the carrier may
suitably comprise a solution, emulsion, ointment or gel base. The
base, for example, may comprise one or more of the following:
petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil,
diluents such as water and alcohol, and emulsifiers and
stabilizers. Thickening agents may be present in a pharmaceutical
composition for topical administration. If intended for transdermal
administration, the composition may include a transdermal patch or
iontophoresis device. Topical formulations may contain a
concentration of the compound of the invention from about 0.1 to
about 10% w/v (weight per unit volume).
[0680] The pharmaceutical composition of the invention may be
intended for rectal administration, in the form, for example, of a
suppository, which will melt in the rectum and release the drug.
The composition for rectal administration may contain an oleaginous
base as a suitable nonirritating excipient. Such bases include,
without limitation, lanolin, cocoa butter and polyethylene
glycol.
[0681] The pharmaceutical composition of the invention may include
various materials, which modify the physical form of a solid or
liquid dosage unit. For example, the composition may include
materials that form a coating shell around the active ingredients.
The materials that form the coating shell are typically inert, and
may be selected from, for example, sugar, shellac, and other
enteric coating agents. Alternatively, the active ingredients may
be encased in a gelatin capsule.
[0682] The pharmaceutical composition of the invention in solid or
liquid form may include an agent that binds to the compound of the
invention and thereby assists in the delivery of the compound.
Suitable agents that may act in this capacity include a monoclonal
or polyclonal antibody, a protein or a liposome.
[0683] The pharmaceutical composition of the invention may consist
of dosage units that can be administered as an aerosol. The term
aerosol is used to denote a variety of systems ranging from those
of colloidal nature to systems consisting of pressurized packages.
Delivery may be by a liquefied or compressed gas or by a suitable
pump system that dispenses the active ingredients. Aerosols of
compounds of the invention may be delivered in single phase,
bi-phasic, or tri-phasic systems in order to deliver the active
ingredient(s). Delivery of the aerosol includes the necessary
container, activators, valves, subcontainers, and the like, which
together may form a kit. One of ordinary skill in the art, without
undue experimentation may determine preferred aerosols.
[0684] The pharmaceutical compositions of the invention may be
prepared by methodology well known in the pharmaceutical art. For
example, a pharmaceutical composition intended to be administered
by injection can be prepared by combining a compound of the
invention with sterile, distilled water so as to form a solution. A
surfactant may be added to facilitate the formation of a
homogeneous solution or suspension. Surfactants are compounds that
non-covalently interact with the compound of the invention so as to
facilitate dissolution or homogeneous suspension of the compound in
the aqueous delivery system.
[0685] The compounds of the invention, or their pharmaceutically
acceptable salts, are administered in a therapeutically effective
amount, which will vary depending upon a variety of factors
including the activity of the specific compound employed; the
metabolic stability and length of action of the compound; the age,
body weight, general health, sex, and diet of the patient; the mode
and time of administration; the rate of excretion; the drug
combination; the severity of the particular disorder or condition;
and the subject undergoing therapy. Generally, a therapeutically
effective daily dose is (for a 70 kg mammal) from about 0.001 mg/kg
(i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 gm); preferably a
therapeutically effective dose is (for a 70 kg mammal) from about
0.01 mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5 gm); more
preferably a therapeutically effective dose is (for a 70 kg mammal)
from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75
gm).
[0686] Compounds of the invention, or pharmaceutically acceptable
salts thereof, may also be administered simultaneously with, prior
to, or after administration of one or more other therapeutic
agents. Such combination therapy includes administration of a
single pharmaceutical dosage formulation which contains a compound
of the invention and one or more additional active agents, as well
as administration of the compound of the invention and each active
agent in its own separate pharmaceutical dosage formulation. For
example, a compound of the invention and the other active agent can
be administered to the patient together in a single oral dosage
composition such as a tablet or capsule, or each agent administered
in separate oral dosage formulations. Where separate dosage
formulations are used, the compounds of the invention and one or
more additional active agents can be administered at essentially
the same time, i.e., concurrently, or at separately staggered
times, i.e., sequentially; combination therapy is understood to
include all these regimens.
Preparation of the Compounds of the Invention
[0687] The following Reaction Scheme illustrates methods to make
compounds of this invention, i.e., compounds of formula (I):
##STR00055##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are described
above in the Summary of the Invention for compounds of formula (I),
as isolated stereoisomers or mixtures thereof, as tautomers or
mixtures thereof, or as pharmaceutically acceptable salts or
N-oxides. In particular, the following Reaction Scheme illustrates
methods to make compounds of formula (Ia):
##STR00056##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
described above in the Summary of the Invention for compounds of
formula (Ia), as isolated stereoisomers or mixtures thereof, as
tautomers or mixtures thereof, or as pharmaceutically acceptable
salts or N-oxides, and methods to make compounds of formula
(Ib);
##STR00057##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
described above in the Summary of the Invention for compounds of
formula (Ib), as isolated stereoisomers or mixtures thereof, as
tautomers or mixtures thereof, or as pharmaceutically acceptable
salts or N-oxides. It is understood that in the following Reaction
Schemes, combinations of substituents and/or variables of the
depicted formulae are permissible only if such contributions result
in stable compounds.
[0688] It will also be appreciated by those skilled in the art that
in the processes described below the functional groups of
intermediate compounds may need to be protected by suitable
protecting groups. Such functional groups include hydroxy, amino,
mercapto and carboxylic acid. Suitable protecting groups for
hydroxy include trialkylsilyl or diarylalkylsilyl (for example,
t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),
tetrahydropyranyl, benzyl, and the like. Suitable protecting groups
for amino, amidino and guanidino include benzyl, t-butoxycarbonyl,
benzyloxycarbonyl, and the like. Suitable protecting groups for
mercapto include --C(O)--R'' (where R'' is alkyl, aryl or
arylalkyl), p-methoxybenzyl, trityl and the like. Suitable
protecting groups for carboxylic acids include alkyl, aryl or
arylalkyl esters.
[0689] Protecting groups may be added or removed in accordance with
standard techniques, which are known to one of ordinary skill in
the art and as described herein.
[0690] The use of protecting groups is described in detail in
Greene, T. W. and P. G. M. Wuts, Greene's Protective Groups in
Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the
art would appreciate, the protecting group may also be a polymer
resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride
resin.
[0691] It will also be appreciated by those skilled in the art,
although such protected derivatives of compounds of this invention
may not possess pharmacological activity as such, they may be
administered to a mammal and thereafter metabolized in the body to
form compounds of the invention which are pharmacologically active.
Such derivatives may therefore be described as "prodrugs". All
prodrugs of compounds of this invention are included within the
scope of the invention.
[0692] It is understood that one of ordinary skill in the art would
be able to make the compounds of the invention by methods similar
to the methods described herein or by methods known to one of
ordinary skill in the art. It is also understood that one of
ordinary skill in the art would be able to make in a similar manner
as described below other compounds of formula (I) not specifically
illustrated below by using the appropriate starting components and
modifying the parameters of the synthesis as needed. In general,
starting components may be obtained from sources such as Sigma
Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific,
TCI, and Fluorochem USA, etc. or synthesized according to sources
known to those skilled in the art (see, for example, Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure, 5th
edition (Wiley, December 2000)) or prepared as described in this
invention. .sup.1H NMR spectra were recorded in CDCl.sub.3,
DMSO-d.sub.6, CD.sub.3OD, Acetone-d.sub.6 with trimethylsilane
(TMS) as internal reference using Gemini 300 MHz instrument.
Reagents and solvents were purchased from commercial sources and
used without further purification. Flash column chromatography was
conducted using silica gel (230-400 mesh) under a positive pressure
of nitrogen. LCMS spectra for purity and mass were recorded using
Waters LCMS instruments. Deionized water was used to dilute the
reactions and wash the products. Brine used was prepared by
dissolving sodium chloride into deionized water to saturation
point.
[0693] Compounds of formula (Ia), as set forth below in Reaction
Scheme 1 below, where R.sup.1, R.sup.2 and R.sup.3 are as defined
above in the Summary of the Invention for compounds of formula (I)
and R.sup.4 and R.sup.5 are hydrogen, are generally prepared as
illustrated below in Reaction Scheme 1 where R.sup.1, R.sup.2 and
R.sup.3 are as defined above in the Summary of the Invention for
compounds of formula (I):
##STR00058##
[0694] Compounds of formula (A), formula (B) and formula (D) are
commercially available or can be prepared by methods known to one
skilled in the art or by methods disclosed herein.
[0695] In general, compounds of formula (Ia) are prepared, as set
forth by Reaction Scheme 1, by first treating a compound of formula
(A) (1.1 equiv) with an equivalent amount of an aniline of formula
(B) in an polar solvent, including, but not limited to, isopropyl
alcohol, at ambient temperatures overnight. The diarylisourea
product of formula (C) generally precipitates and isolation can be
accomplished via filtration, washing with an appropriate solvent,
and drying. Hydrazine hydrate of formula (D) (2 equivalents) is
added to a slurry of the compound of formula (C) in an alcohol or
other appropriate solvent. Generally, the ring formation reaction
occurs at ambient temperature and the product triazole of formula
(Ia) can be isolated by standard isolation techniques. Compounds of
formula (Ia) can be subsequently treated with an appropriately
substituted alkylating or acylating agent under standard conditions
to form compounds of formula (Ia) where R.sup.4 and R.sup.5 are as
described above in the Summary of the Invention for compounds of
formula (I).
[0696] Compounds of formula (Ib) can be prepared using the
synthetic route outlined in Reaction Scheme 1 in varying amounts
depending on the steric and electronic nature of R.sup.1, R.sup.2
and R.sup.3 as well as the particular reaction conditions employed.
In some instances, compounds of formula (Ib) are isolated as minor
isomers along with compounds of formula (Ia) as major isomers,
e.g., during column chromatography, as described herein.
[0697] Compounds of formula (C-1) are compounds of formula (C), as
shown above in Reaction Scheme 1, where R.sup.1 is hydrogen and
R.sup.2 is
5',5'-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,-
3]dioxane]-3-yl, that is, where R.sup.2 has the following
structure:
##STR00059##
Compounds of formula (C-1) can be prepared according to the method
described below in Reaction Scheme 2:
##STR00060##
[0698] Compounds of formula (Ca) and (Cb) are commercially
available or can be prepared according to methods known to one
skilled in the art.
[0699] In general, compounds of formula (C-1) are prepared, as set
forth above in Reaction Scheme 2, by first heating a mixture of the
compound of formula (Ca) (1.0 equiv) and a compound of formula (Cb)
(0.96 equiv) and ammonia in an protic solvent, such a methanol, to
reflux temperature. The compound of formula (Cc) is then isolated
from the reaction mixture by standard isolation techniques.
[0700] The compound of formula (Cc) is then reduced under standard
reduction conditions known to one skilled in the art to yield the
compound of formula (Cd).
[0701] A mixture of molar equivalent amounts of the compound of
formula (Cd), diphenylcyanocarboimidate and diisopropylethylamine
in a protic solvent, such as isopropyl alcohol, is stirred at
ambient temperature for a period of time of between 8 hours and 16
hours, preferably for about 16 hours, to form the compound of
formula (C-1), which is isolated from the reaction mixture by
standard isolation techniques known to one skilled in the art.
[0702] Compounds of formula (Da) are compounds of formula (D), as
shown above in Reaction Scheme 1, where R.sup.3 is a tricyclic
heteroaryl of the following formula:
##STR00061##
Compounds of formula (Da) can be prepared according to the method
disclosed below in Reaction Scheme 3.
##STR00062##
[0703] Compounds of formula (Da) are commercially available or can
be prepared by methods known to one skilled in the art or by
methods disclosed herein.
[0704] In general, compounds of formula (D-1) are prepared, as set
forth above in Reaction Scheme 3, by first dissolving the compound
of formula (Da) (1.0 equiv) in an anhydrous aprotic polar solvent
or mixture of such solvents, for example, tetrahydrofuran with
hexamethylphosphoramide (HMPA) (1.2 equiv). The resulting solution
is stirred at ambient temperature for about 10 minutes and then
cooled to a temperature of between about -10.degree. C. and about
5.degree. C., preferably at 0.degree. C. A strong base, lithium
bis(trimethylsilyl)amide (Li-HMDS) (1.1 equiv), is then added
dropwise to the stirred mixture over a period of time of between
about 20 minutes and 40 minutes, preferably over 30 minutes, while
maintaining the temperature of the resulting mixture at between
about -10.degree. C. and about 5.degree. C., preferably at
0.degree. C. Ethyl bromoacetate (2.5 equiv) is then added to the
resulting anion of (Da) and the resulting mixture is stirred for
additional period of time of between about 5 minutes and 15
minutes, preferably for about 10 minutes, and then allowed to warm
to ambient temperature and stirred at ambient temperature for a
period of time of between about 30 minutes and 3 hours, preferably
for about 2 hours. The compound of formula (Db) is then isolated
from the reaction mixture by standard isolation techniques known to
one skilled in the art, such as solvent evaporation and
purification by flash column chromatography.
[0705] The compound of formula (Db) is then treated under basic
hydrolysis conditions to form the compound of formula (Dc), which
is isolated from the reaction mixture by standard isolation
techniques known to one skilled in the art.
[0706] The compound of formula (Dc) (1.0 equiv) is then treated
with hydrazine hydrate (1.25 equiv) in the presence of a polar
protic solvent, such as ethanol, to yield the compound of formula
(Dd), which is isolated from the reaction mixture by standard
isolation techniques known to one skilled in the art.
[0707] A mixture of the compound of formula (Dd) (1.0 equiv) and
anhydrous copper(II) chloride (2.0 equiv) is then refluxed in
acetonitrile to yield the unsaturated compound of formula (De),
which is isolated from the reaction mixture by standard isolation
techniques known to one skilled in the art.
[0708] A mixture of the compound of formula (De) and phosphoryl
chloride, is refluxed for a period of time of between about 1 hour
and 3 hours, preferably for about 2 hours to aromatize and
chlorinate the ring containing the N--N linkage. After cooling to
ambient temperature, the compound of formula (Df) is isolated from
the reaction mixture by standard isolation techniques known to one
skilled in the art.
[0709] Skilled artisans would appreciate that the compound of
formula (Df) can be used to make the corresponding 3-aniline which
can be used as an aniline of formula (B), as outlined in Reaction
Scheme 1 above, to make additional embodiments of the
invention.
[0710] A mixture of the compound of formula (Df) (1.0 equiv) and
anhydrous hydrazine (19.8 equiv) in a protic solvent, such as
ethanol, is refluxed for a period time of between about 4 hours and
24 hours, preferably for about 16 hours. After cooling to ambient
temperature, water is added to the mixture and the compound of
formula (D-1) is then isolated from the reaction mixture by
standard isolation techniques known to one skilled in the art.
[0711] All compounds of the invention which exist in free base or
acid form can be converted to their pharmaceutically acceptable
salts by treatment with the appropriate inorganic or organic base
or acid by methods known to one of ordinary skill in the art. Salts
of the compounds of the invention can be converted to their free
base or acid form by standard techniques known to one skilled in
the art.
[0712] The following specific Synthetic Preparations (for
intermediates) and Synthetic Examples (for compounds of the
invention) are provided as a guide to assist in the practice of the
invention, and are not intended as a limitation on the scope of the
invention. The number following each compound below refers to its
number in Table 1, as discussed in more detail below.
SYNTHETIC PREPARATION 1
Compound of Formula (Cc)
[0713] A mixture of 3,3-dimethyl-1,5-dioxaspiro[5.7]tridecan-10-one
(compound of formula (Ca)) (1.32 g, 5.83 mmol),
1-methyl-3,5-dinitro-1H-pyridin-2-one (compound of formula (Cb))
(1.07 g, 5.3 mmol) and 7N ammonia solution in methanol (45 mL) was
heated at 80.degree. C. in sealed vessel overnight. The solvent was
evaporated and the residue was dissolved in dichloromethane (DCM).
The soluble portion was concentrated and purified by flash
chromatography on silica gel (hexane/ethyl acetate, 3:1) to give
the compound of formula (Cc),
5',5'-dimethyl-3-nitro-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine--
7,2'-[1,3]dioxane] (1.5 g, 92.5%); .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 9.09 (s, 1H), 8.40 (s, 1H), 3.37 (m, 4H), 3.02 (t, 2H), 2.89
(m, 2H), 2.02 (m, 2H), 1.77 (m, 2H), 1.58 (t, 2H), 0.86 (d, 6H)
ppm; MS (ES) 306.99 (M+H).
SYNTHETIC PREPARATION 2
Compound of Formula (Cd)
[0714] The compound of formula (Cc),
5',5'-dimethyl-3-nitro-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine--
7,2'-[1,3]dioxane], was hydrogenated in ethanol/THF solution over
10% Pd/C for 1 hour at 40 psi to give the compound of formula (Cd),
5',5'-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,-
3]dioxan]-3-amine, in quantitative yield; MS (ES) 277.67
(M+2H).
SYNTHETIC PREPARATION 3
Compound of Formula (C-1)
[0715] A mixture of the compound of formula (Cd),
5',5'-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,-
3]dioxan]-3-amine (1.08 g, 3.9 mmol), diphenylcyanocarboimidate
(0.93 g, 3.9 mmol), diisopropylethylamine (680 .mu.l, 3.9 mmol) and
isopropyl alcohol (15 mL) was stirred at ambient temperature
overnight. The solvent was evaporated, and the residue was purified
by flash chromatography on silica gel (ethyl acetate) to the
compound of formula (C-1), phenyl
N'-cyano-N-(5',5'-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyrid-
ine-7,2'-[1,3]dioxane]-3-yl)carbamimidate, (1.09 g, 66.8%); .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) 10.81 (s, 1H), 8.36 (s, 1H), 7.64 (s,
1H), 7.42 (t, 2H), 7.28 (m, 3H), 3.37 (m, 4H), 2.87 (t, 2H), 2.73
(m, 2H), 1.97 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H), 0.85 (d, 6H)
ppm; MS (ES) 421.01 (M+H).
SYNTHETIC PREPARATION 4
Synthesis of ethyl
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate
Compound of Formula (Db)
[0716] To a mixture of 1-benzosuberone (5.0 g, 31.2 mmol, Aldrich)
in dry tetrahydrofuran (THF) (20 mL) was added
hexamethylphosphoramide (6.5 mL, 37.5 mmol) (99%, Aldrich). The
resulting mixture was stirred at ambient temperature for 10 min and
then cooled to 0.degree. C. with a ice-water bath, 1.0 M solution
of lithium bis(trimethylsilyl)-amide in THF (32.7 mL, 32.7 mmol)
was added dropwise in 30 min. After the addition, the reaction
mixture was stirred at 0.degree. C. for 30 min. Ethyl bromoacetate
(8.7 mL, 78.1 mmol) was then added. After stirring for a further 10
min, the reaction mixture was warmed to ambient temperature and
stirred for 2 h. Solvent was evaporated, the residue was diluted
with ethyl acetate (EtOAc) (300 mL), and washed with water and
brine. After being dried (MgSO.sub.4), filtered, and concentrated,
the residue was purified by flash column chromatography eluting
with hexanes-ethyl acetate 6:1.fwdarw.4:1) to afford 6.6 g of the
compound of formula (Db), ethyl
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate, as an
orange oil (84%), .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.:
7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1H), 3.12-2.92
(m, 3H), 2.52-2.43 (m, 1H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H);
LC-MS: purity: 91.8%; MS (m/e): 247 (MH.sup.+).
SYNTHETIC PREPARATION 5
Synthesis of
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetic acid
Compound of formula (Dc)
[0717] The compound of formula (Db), ethyl
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate, (6.6
g, 26.8 mmol) was dissolved in ethanol (EtOH) (30 mL), then 10%
potassium hydroxide (KOH) aqueous solution (37.5 mL, 67 mmol) was
added and the resulting mixture was refluxed for 2 h. After cooling
to ambient temperature, the EtOH was removed by evaporation. The
residue was extracted with EtOAc twice (15 mL.times.2). The aqueous
layer was then transferred into a flask and cooled with an
ice-water bath, con. HCl was added dropwise to adjust pH to about
2.0. EtOAc (60 mL) was then added, the layers were separated, and
the aqueous layer was extracted with EtOAc. The combined extracts
were washed with brine. After being dried (MgSO.sub.4), filtered,
and concentrated, the compound of formula (Dc),
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetic acid,
was obtained as an orange oil (5.7 g, 97%); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.: 7.71-7.68 (m, 1H), 7.41-7.20 (m, 3H),
3.37-3.31 (m, 1H), 3.12-2.91 (m, 3H), 2.57-2.49 (m, 1H), 2.15-1.90
(m, 2H), 1.75-1.62 (m, 2H); LC-MS: purity: 100%; MS (m/e): 219
(MH.sup.+).
SYNTHETIC PREPARATION 6
Synthesis of
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one
Compound of formula (Dd)
##STR00063##
[0719] A. A mixture of the compound of formula (Dc),
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetic acid,
(5.7 g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20
mL of ethanol was refluxed for 2 h, cooled and filtered (washed
with small amount of EtOH) to give the compound of formula (Dd),
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one,
as a white solid (4.7 g, 84%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 8.61 (bs, 1H), 7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58
(dd, J=15.3, 16.8 Hz, 1H), 2.31 (dd, J=12.0, 16.8 Hz, 1H),
1.96-1.59 (m, 4H); LC-MS: purity: 100%; MS (m/e): 215
(MH.sup.+).
[0720] B. Alternatively, a mixture of benzosuberone (10.6 g, 66.2
mmol), glyoxylic acid monohydrate (6.08 g, 66.2 mMol), sodium
hydroxide (10.6 g, 265 mmol), ethanol (40 mL) and water (100 mL)
were stirred overnight at ambient temperature, and then heated
under reflux for 1 h. The mixture was cooled, then diluted with
water and extracted twice with dichloromethane (subsequently
discarded). The aqueous layer was then acidified with 10% aqueous
hydrochloric acid. Ice was added for cooling. The mixture was then
filtered to give a pale yellow solid, 10.5 g (after air drying).
The crude solid was then heated at 100.degree. C. for 1 h with a
mixture of acetic acid (60 mL), water (30 mL) and zinc dust (6 g).
The reaction mixture was cooled to ambient temperature and
filtered. The filtrate was extracted with ethyl acetate. The
organic layer was washed three times with saturated sodium chloride
solution, then dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude residue was heated with ethanol (25 mL) and
hydrazine monohydrate (10 mL) under reflux for 3 h. The solvent was
removed under vacuum and the residue was crystallized from
benzene/ethanol, 1/1, to give
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one
as a white solid, 2.31 g; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.66
(s, 1H), 7.52 (d, 1H), 7.24-7.50 (m, 2H), 7.16 (d, 2H), 2.75-3.00
(m, 3H), 2.56 (dd, 1H), 2.31 (dd, 1H), 1.60-1.90 (m, 4H) ppm; MS
(ES) 215 (M+H). This procedure followed that reported by V.
Peesapati and S. C. Venkata, Indian J. Chem., 41B, 839 (2002).
SYNTHETIC PREPARATION 7
Synthesis of
3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine
Compound of Formula (De)
##STR00064##
[0722] A. A mixture of the compound of formula (Dd),
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one
(4.7 g, 22 mmol) and anhydrous copper(II) chloride (6 g, 44 mmol)
was refluxed in acetonitrile (45 mL) for 2 hours. After cooling to
ambient temperature, the mixture was poured into ice-water (200 g)
and the solid obtained was washed with 10% HCl solution twice
(about 20 mL.times.2) and cold water twice (about 20 mL.times.2).
After freeze-drying, the compound of formula (De),
3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (4.2 g,
90%) was obtained as a white solid, .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.: 10.80 (bs, 1H), 7.53-7.21 (m, 4H), 6.77 (s,
1H), 2.66 (t, J=6.9 Hz, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.14 (quant,
J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 213 (MH.sup.+).
[0723] B. Alternatively, a solution of
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one
(2.31 g, 10.74 mmol), sodium m-nitrobenzenesulfonate (2.48 g, 11
mmol), sodium hydroxide (1.86 g, 46.5 mmol) in water (80 mL) was
heated under reflux for 1.5 h. The solution was cooled to ambient
temperature, and then acidified with concentrated hydrochloric
acid. The solid which precipitated was filtered off, washed with
water and crystallized from ethanol to give
3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as tan
crystals, 1.46 g; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 13.04 (s,
1H), 7.25-7.45 (m, 4H), 6.78 (s, 1H), 2.49 (m, 2H), 2.35 (m, 2H),
2.04 (m, 2H) ppm; MS (ES) 213 (M+H).
SYNTHETIC PREPARATION 8
Synthesis of
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine
Compound of Formula (Df)
##STR00065##
[0725] A. A mixture of the compound of formula (De),
3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (4.0 g,
19.3 mmol) and POCl.sub.3 (20 mL) was refluxed for 2 h. After
cooling to ambient temperature, the volatiles were evaporated. The
residue was poured into a mixture of ice water and sodium
bicarbonate, CH.sub.2Cl.sub.2 (200 mL) was added to dissolve the
solid. The layers were separated, and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 one more time. The combined organic
layers were washed with brine. After being dried (MgSO.sub.4),
filtered, and concentrated, the compound of formula (Df),
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine was
obtained as a yellow solid (4.3 g, 99%), .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.: 7.82 (m, 1H), 7.45-7.24 (m, 4H), 2.59-2.51 (m,
4H), 2.27 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 231
(MH.sup.+).
[0726] B. Alternatively,
3-Oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine was
heated with 20 mL of phosphorus (III) oxychloride at 100.degree. C.
for 4.75 h. The solvent was removed under vacuum. The residue was
treated with ice and saturated sodium bicarbonate solution. The
solid which formed was filtered off, washed well with water and
air-dried to yield the corresponding
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6
g); .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H),
7.39 (s, 1H), 7.27 (m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES)
231/233 (M+H).
SYNTHETIC PREPARATION 9
Synthesis of
3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine
Compound of Formula (D-1)
##STR00066##
[0728] A. A mixture of the compound of formula (Df),
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.3
g, 18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL
of ethanol was refluxed for 16 h. After cooling to ambient
temperature, 5 mL of water was added and the volatiles were then
evaporated. To the solid residue was added cold water (about 80
mL). After sonication for 10 min, the resulting solid was collected
by filtration and washed with cold water three times. After
freeze-drying, the compound of formula (D-1),
3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine,
(4.14 g, 98%) was obtained as a slight yellow solid, .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta.: 7.59 (m, 1H), 7.39-7.26 (m, 3H),
7.04 (s, 1H), 2.54 (t, J=6.9 Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 2.18
(quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 227
(MH.sup.+).
[0729] B. Alternatively,
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6
g) was heated with anhydrous hydrazine (4 mL) in ethanol (50 mL) at
100.degree. C. for 4.75 h. The solvent was removed under vacuum.
The residue was partitioned between chloroform and 1M saturated
aqueous potassium carbonate. The organic layer was dried over
anhydrous sodium sulfate and concentrated under vacuum to give
3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as
a brown solid; .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.74 (m, 1H), 7.30
(m, 2H), 7.17 (m, 1H), 6.92 (s, 1H), 2.49 (m, 2H), 2.39 (m, 2H),
2.12 (m, 2H) ppm; MS (ES) 227 (M+H).
SYNTHETIC EXAMPLE 1
Synthesis of
N.sup.3-(3-Fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
##STR00067##
[0730] A. Synthesis of
5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2-amine
##STR00068##
[0732] Cyclooctanone (5.0 g, 39.7 mmol) and t-butoxy
bis(dimethylamino)methane (6.9 g, 39.7 mmol) were heated at
100.degree. C. for 18 h. The solvent was removed under vacuum. The
crude residue was taken up in anhydrous ethanol (80 mL). Guanidine
hydrochloride (7.6 g, 0.08 Mol, 2 eq.) and sodium metal (1.84 g,
0.08 Mol) were added. After the sodium dissolved, the mixture was
heated to reflux for 41 h. After cooling to ambient temperature,
sodium metal (0.47 g) and guanidine hydrochloride (1.5 g) were
added and heating was resumed for another 23 h. The reaction
mixture was concentrated under vacuum and then partitioned between
chloroform and water. The aqueous layer was extracted once with
chloroform. The combined organic layers were washed with saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate and concentrated under vacuum to give
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-amine as a pale
yellow solid, 5.51 g; .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.92 (s,
1H), 5.19 (br s, 2H), 2.67 (m, 2H), 2.57 (m, 2H), 1.74 (m, 2H),
1.59 (m, 2H), 1.25-1.50 (m, 4H) ppm; .sup.13C NMR (CDCl.sub.3, 75
MHz) 170.41, 162.09, 157.55, 123.62, 34.19, 32.60, 30.14, 28.64,
26.30, 26.05; MS (ES) 178 (M+H). The aniline,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-amine, can be used to
make the corresponding hydrazine as outlined below, or
alternatively, can be used as an aniline (B) as outlined in
Reaction Scheme 1 above.
B. Synthesis of
5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2(3H)-one
##STR00069##
[0734] 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2-amine (5.51 g)
was heated under reflux in 50% aqueous hydrochloric acid (80 mL)
for 23 h. The reaction mixture was concentrated under vacuum. The
residue was partitioned between saturated sodium bicarbonate
solution and chloroform. The organic layer was dried over anhydrous
sodium sulfate and concentrated under vacuum to give
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2(3H)-one as a white
solid; MS (ES) 179 (M+H)
C. Synthesis of
2-Chloro-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine
##STR00070##
[0736] Crude 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2(3H)-one
was heated in phosphorus (III) oxychloride (50 mL) for 1.75 h. The
solvent was removed under vacuum and the residue was treated with
ice water and 1M aqueous potassium carbonate solution, the aqueous
layer was extracted with a mixture of diethyl ether and ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate
and concentrated under vacuum to give
2-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine as a yellow
solid, 1.5 g; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.18 (s, 1H), 2.82
(m, 2H), 2.66 (m, 2H), 1.74 (m, 2H), 1.61 (m, 2H), 1.34 (m, 4H)
ppm; .sup.13C NMR (CDCl.sub.3, 75 MHz) 173.25, 158.66 (2C), 132.74,
34.28, 32.03, 30.20, 28.57, 26.02, 25.90; MS (ES) 197/199
(M+H).
D. Synthesis of
2-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine
##STR00071##
[0738] 2-Chloro-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine (1.5
g) was treated with anhydrous pyridine (15 mL) and anhydrous
hydrazine (7 mL) at 120.degree. C. for 3.75 h. The solvent was
removed under vacuum. The residue was partitioned between
chloroform and 1M aqueous potassium carbonate solution. The organic
layer was dried over anhydrous sodium sulfate and concentrated
under vacuum to give
2-hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine as a
beige solid, 1.28 g; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.00 (s,
1H), 6.63 (br s, 1H), 3.93 (br s, 2H), 2.76 (m, 2H), 2.60 (m, 2H),
1.74 (m, 2H), 1.63 (m, 2H), 1.40 (m, 4H) ppm; .sup.13C NMR
(CDCl.sub.3, 75 MHz) 170.57, 163.81, 157.22, 124.14, 34.31, 32.65,
30.24, 28.66, 26.32, 26.08; MS (ES) 193 (M+H).
E. Synthesis of
N.sup.3-(3-Fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
[0739] 2-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine
(58 mg, 0.30 mmol) and (Z)-phenyl
N'-cyano-N-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)carbamimidate
(111 mg, 0.30 mmol) were dissolved in anhydrous N-methylpyrrolidone
(0.5 mL) and subjected to microwave irradiation (220.degree. C., 10
min). The crude reaction mixture was directly purified by C-18
reversed phase chromatography, eluting with acetonitrile and water
containing 0.05% formic acid to give
N.sup.3-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #4, as a beige solid, 30 mg; .sup.1H NMR
(CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.22 (s, 1H), 8.19 (s, 1H), 7.26
(d, 1H), 6.93 (d, 1H), 6.71 (t, 1H), 3.23 (m, 6H), 3.16 (m, 2H),
2.81 (m, 2H), 2.69 (s, 3H), 2.61 (m, 2H), 2.12 (m, 2H), 1.69 (m,
2H), 1.56 (m, 2H), 1.27 (m, 4H) ppm; MS (ES) 466.27 (M+H).
SYNTHETIC EXAMPLE 2
Synthesis of
N.sup.3-(4-(4-Cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine
##STR00072##
[0740] A. Synthesis of
3-Chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine
##STR00073##
[0742] Cyclooctanone (6.31 g, 51 mmol) and glyoxylic acid
monohydrate (4.6 g, 51 mmol) were heated neat at 50.degree. C. for
5.25 h, following the procedure of K. Ueno et. al., Heterocycles,
57, 723 (2002). Hydrazine hydrate (3.6 mL) was added and heating
continued for 1 h. The reaction mixture was cooled to ambient
temperature and the solid which precipitated was filtered off,
washed well with diethyl ether and air dried. The crude waxy yellow
solid was then heated with excess phosphorus (III) oxychloride at
100.degree. C. for 2.25 h. The solvent was removed under vacuum and
the residue was treated with ice water, then 1M aqueous potassium
carbonate solution. The aqueous layer was extracted with a mixture
of ethyl acetate and methanol. The organic layer was dried over
anhydrous sodium sulfate and concentrated under vacuum. The crude
product was passed over a pad of silica gel, eluting with 1/1
hexanes/ethyl acetate to give
3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine as a brown
oil, 1.36 g; .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.17 (s, 1H), 3.07
(m, 2H), 2.70 (m, 2H), 1.79 (m, 2H), 1.72 (m, 2H), 1.34 (m, 4H)
ppm; .sup.13C NMR (CDCl.sub.3, 75 MHz) 163.61, 155.01, 144.37,
127.40, 32.23, 31.71, 31.45, 30.94, 26.07, 25.82; MS (ES) 197/199
(M+H).
B. Synthesis of
3-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine
##STR00074##
[0744] 3-Chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine (1.36
g) was treated with anhydrous pyridine (10 mL) and anhydrous
hydrazine (3 mL) at 100.degree. C. for 5.5 h. The solvent was
removed under vacuum and the residue was partitioned between
chloroform and saturated aqueous potassium carbonate solution. The
organic layer was dried over anhydrous sodium sulfate and
concentrated under vacuum to provide
3-hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine; .sup.1H
NMR (CDCl.sub.3, 300 MHz) 6.71 (s, 1H), 3.01 (m, 2H), 2.68 (m, 2H),
1.70-1.85 (m, 4H), 1.40 (m, 4H) ppm; MS (ES) 193 (M+H).
C. Synthesis of
N.sup.3-(4-(4-Cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine
##STR00075##
[0746] 3-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine
(101 mg, 0.53 mmol) and (Z)-phenyl
N'-cyano-N-(4-(4-cyclohexylpiperazin-1-yl)phenyl)carbamimidate (212
mg, 0.53 mmol) were suspended in isopropanol (3 mL) and subjected
to microwave irradiation (150.degree. C., 20 min). A portion of the
crude product was purified by C-18 reversed phase hplc to give
N.sup.3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine, compound
#16, 17 mg. .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.41 (s, 1H), 7.55
(d, 2H), 6.92 (d, 2H), 3.38 (m, 3H), 3.15 (m, 6H), 2.96 (m, 1H),
2.80 (m, 2H), 2.11 (m, 2H), 1.67-1.90 (m, 7H), 1.05-1.45 (m, 10H)
ppm; MS (ES) 502.28 (M+H).
SYNTHETIC EXAMPLE 3
Synthesis of
1-(5,6,7,8,9,10-Hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(4-methylpi-
perazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine
##STR00076##
[0747] A. Synthesis of
5,6,7,8,9,10-Hexahydrocycloocta[b]pyridin-2(1H)-one
##STR00077##
[0749] Ammonia gas was bubbled vigorously into anhydrous methanol
(200 mL) for 10 min. Then methyl propiolate (7.26 g, 86.3 mmol) and
cyclooctanone (9.4 g, 74.5 mmol) were added. The solution was
heated in a stainless steel bomb at 100.degree. C. for 6 h, and
then allowed to cool to ambient temperature overnight. The solvent
was removed under vacuum and the residue was purified by flash
chromatography on silica gel, eluting with 96% dichloromethane and
4% 2M ammonia in methanol solution to give
5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(1H)-one; .sup.1H NMR
(CDCl.sub.3, 300 MHz) 7.21 (d, 1H), 6.37 (d, 1H), 2.73 (m, 2H),
2.48 (m, 2H), 1.86 (m, 2H), 1.76 (m, 2H), 1.40 (m, 4H) ppm; MS (ES)
178 (M+H).
B. Synthesis of
2-Chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
##STR00078##
[0751] 5,6,7,8,9,10-Hexahydrocycloocta[b]pyridin-2(1H)-one was
heated with excess phosphorus (III) oxychloride at 100.degree. C.
for 8 h. The solvent was removed under vacuum. The residue was
treated with ice and 1M aqueous potassium carbonate solution, and
then extracted with chloroform. The organic layer was dried over
anhydrous sodium sulfate and concentrated under vacuum. Flash
chromatography on silica gel, eluting with a mixture of 96%
dichloromethane and 4% methanol gave
2-chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine as a brown oil;
.sup.1H NMR (CDCl.sub.3, 300 MHz) 7.32 (d, 1H), 7.06 (d, 1H), 2.92
(m, 2H), 2.74 (m, 2H), 1.79 (m, 2H), 1.69 (m, 2H), 1.38 (m, 4H)
ppm; .sup.13C NMR (CDCl.sub.3, 75 MHz) 161.86, 147.73, 140.19,
135.65, 122.26, 34.33, 32.30, 31.52, 30.83, 26.26, 26.14; MS (ES)
196/198 (M+H).
C. Synthesis of
2-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
##STR00079##
[0753] 2-Chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine was
treated with ethanol (20 mL) and anhydrous hydrazine (5 mL) in a
sealed tube at 150.degree. C. bath temperature for 7 h. Initial
experiments showed that the addition did not proceed in boiling
ethanol at atmospheric pressure. HPLC showed that the addition was
incomplete, so the reaction mixture was heated at 150.degree. C.
for a further 7 h. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography on silica gel,
eluting with 95% dichloromethane and 5% of a 2M solution of ammonia
in methanol; .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.19 (d, 1H), 6.51
(d, 1H), 5.85 (br s, 1H), 3.77 (br s, 2H), 2.79 (m, 2H), 2.63 (m,
2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H) ppm; .sup.13C NMR
(CDCl.sub.3, 75 MHz) 156.87, 158.54, 138.81, 126.67, 104.58, 34.72,
32.67, 31.45, 30.85, 26.41, 26.37; MS (ES) 192 (M+H).
D. Synthesis of
1-(5,6,7,8,9,10-Hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(4-methylpi-
perazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine
##STR00080##
[0755] 2-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (81
mg, 0.42 mmol) and (Z)-phenyl
N'-cyano-N-(4-(4-methylpiperazin-1-yl)phenyl)carbamimidate (142 mg,
0.42 mmol) were suspended in isopropanol and subjected to microwave
irradiation (150.degree. C., 20 min). The crude product was
purified by C-18 reversed phase HPLC to give
1-(5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(4-methylpi-
perazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #23,
as a white solid, 92 mg; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 8.69
(s, 1H), 8.13 (s, 1H), 7.65 (d, 1H), 7.55 (s, 1H), 7.44 (d, 2H),
7.41 (d, 1H), 6.84 (d, 2H), 3.01 (m, 4H), 2.90 (m, 2H), 2.75 (m,
2H), 2.50 (m, 4H), 2.25 (s, 3H), 1.71 (m, 2H), 1.63 (m, 2H), 1.33
(m, 4H) ppm; MS (ES) 433.17 (M+H).
SYNTHETIC EXAMPLE 4
Synthesis of
1-(5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine
##STR00081##
[0756] A. Synthesis of
2-Mercapto-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol
##STR00082##
[0758] 700 mg of NaOEt (10 mmol; 1.0 equiv) was added to 6 mL of
abs. EtOH. To this solution was added, with stirring, 2 g of ethyl
2-keto-cyclooctylcarboxylate (10 mmol; 1.0 equiv) and 1 g of
thiourea (13 mmol; 1.3 equiv). The mixture was refluxed for 6
hours. After cooling, the mixture was poured onto ice and acidified
with hydrochloric acid. 1.33 g of
2-mercapto-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (63%
yield) was obtained as a white solid.
B. Synthesis of
5,6,7,8,9,10-Hexahydrocycloocta[d]-pyrimidine-4-ol
##STR00083##
[0760] A mixture of
2-mercapto-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (1 g;
4.76 mmol) and 10 g of Raney nickel in 40 mL of abs. EtOH was
refluxed for 5 hours and filtered. The filtrate was evaporated to
give 5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol as a
pale-grey solid (0.66 g; 78% yield).
C. Synthesis of
4-Chloro-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine
##STR00084##
[0762] A mixture of
5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (0.66 g; 3.7
mmol; 1.0 equiv) in 3.3 mL of POCl.sub.3 (37 mmol; 10 equiv) was
heated at 100.degree. C. for 2 hours. The reaction was cooled and
poured onto ice. The solution was adjusted to ca. pH 5 with
ammonium hydroxide. The oil was extracted with ether and the
extract was dried over MgSO.sub.4. The solvent was evaporated to
give 4-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine t as a
clear yellow oil (0.71 g; 98% yield).
D. Synthesis of
4-Hydrazino-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine
##STR00085##
[0764] Hydrazine monohydrate (0.21 mL; 4.34 mmol; 1.2 equiv) was
added to a suspension of
4-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine (0.71 g;
3.62 mmol; 1.0 equiv) in 8 mL of EtOH. The reaction was heated at
60.degree. C. overnight. The solid was filtered, washed with
H.sub.2O and dried to give
4-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine as an
off-white solid (0.42 g; 60% yield).
E. Synthesis of
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine
##STR00086##
[0766] A mixture of
N-cyano-N'-{[4-(pyrrolidin-1-yl-ethoxy)]phenyl}-O-phenylisourea (50
mg; 0.14 mmol; 1.0 equiv) and
4-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine (28 mg;
0.14 mmol; 1 equiv) in 1 mL of isopropanol was heated in the
microwave apparatus at 150.degree. C. for 15 min. Purification by
silica gel column chromatography eluted with
CH.sub.2Cl.sub.2/MeOH/Et.sub.3N (95/5/1) gave
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound
#20, as a pale-yellow solid (50 mg; 78% yield); .sup.1H-NMR
(DMSO-d6, 300 MHz) 8.85 (br. s, 1H), 8.71 (s, 1H), 7.53 (br. s,
2H), 7.43 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.7 Hs, 2H), 4.05-3.98 (m,
2H), 3.40-3.22 (m, 4H), 3.00-2.95 (m, 2H), 2.72-2.58 (m, 4H),
1.92-1.83 (m, 2H), 1.78-1.68 (m, 6H), 1.48-1.32 (m, 4H) ppm; MS
(ES) 449.54 (M+H), 447.25 (M-H).
SYNTHETIC EXAMPLE 5
[0767] In a similar manner as described above utilizing the
appropriately substituted starting materials and reagents, the
following compounds of formula (Ia) were prepared: [0768]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #21,
pale-brown solid; MS (ES) 434.42 (M+H); [0769]
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #24, off-white solid; MS (ES) 514.66 (M+H), 512.40 (M-H);
[0770]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound
#1; .sup.1H NMR (CDCl.sub.3, 7300 MHz) 8.31 (s, 1H), 7.32 (d, 2H),
7.16 (br s, 2H), 6.87 (s, 1H), 6.82 (d, 2H), 4.04 (t, 2H),
2.92-2.82 (m, 4H), 2.72 (m, 2H), 2.59 (m, 4H), 1.77 (m, 6H), 1.68
(m, 2H), 1.28 (m, 4H) ppm; .sup.13C NMR (CDCl.sub.3, 75 MHz)
171.12, 158.78, 157.55, 155.74, 154.96, 153.73, 134.34, 129.20,
119.52, 115.40, 67.74, 55.50, 55.01, 34.52, 32.35, 30.38, 28.77,
26.14, 26.02, 23.88; MS (ES) 449.25 (M+H); [0771]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #2;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) 8.70 (s, 1H), 8.47 (s, 1H),
7.60 (s, 2H), 7.45 (d, 2H), 6.82 (d, 2H), 3.00 (m, 2H), 2.90 (m,
2H), 2.75 (m, 2H), 2.48 (m, 6H), 2.21 (s, 3H), 1.82-1.76 (m, 4H),
1.36 (m, 4H) ppm; MS (ES) 434.34 (M+H); [0772]
N.sup.3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydroc-
ycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine, compound
#5; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 8.46 (s, 2H), 7.46 (d, 2H),
7.44 (s, 1H), 6.81 (d, 2H), 2.98 (m, 4H), 2.90 (m, 2H), 2.77 (m,
2H), 2.64 (m, 4H), 2.49 (m, 6H), 2.22 (m, 1H), 1.85-1.50 (m, 6H),
1.39 (m, 3H), 1.26 (m, 3H) ppm; MS (ES) 502 (M+H); [0773]
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #3; .sup.1H NMR (CD.sub.3CN/MeOD.sub.4, 300 MHz) 8.41 (s,
1H), 8.27 (s, 1H), 7.49 (d, 2H), 6.87 (d, 2H), 3.15 (s, 2H), 2.90
(m, 6H), 2.80 (m, 2H), 2.50 (m, 1H), 2.27 (m, 1H), 2.00-1.60 (m,
8H), 1.55-1.15 (m, 10H) ppm; MS (ES) 514.31 (M+H); [0774]
(R)--N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #6; .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.27 (s,
1H), 8.20 (s, 1H), 7.24 (d, 2H), 6.44 (d, 2H), 3.53 (m, 1H), 3.35
(m, 2H), 3.12 (m, 1H), 2.81 (m, 2H), 2.64 (m, 2H), 2.57 (s, 6H),
2.50 (m, 1H), 2.12 (m, 1H), 1.72 (m, 2H), 1.60 (m, 2H), 1.30 (m,
4H) ppm; MS (ES) 448.22 (M+H); [0775]
(S)--N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #7; .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.23 (s,
1H), 8.21 (s, 1H), 7.25 (d, 2H), 6.46 (d, 2H), 3.15-3.40 (m, 5H),
2.84 (M, 2H), 2.68 (m, 2H), 2.49 (s, 6H), 2.24 (m, 1H), 2.06 (m,
1H), 1.75 (m, 2H), 1.62 (m, 2H), 1.33 (m, 4H) ppm; MS (ES) 448.20
(M+H); [0776]
N.sup.3-(3-chloro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #8, .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.25 (s,
1H), 8.19 (s, 1H), 7.45 (d, 1H), 7.20 (dd, 1H), 6.86 (d, 1H), 3.16
(m, 8H), 2.90 (m, 1H), 2.80 (m, 1H), 2.64 (m, 2H), 1.97 (m, 2H),
1.75 (m, 4H), 1.58 (m, 4H), 1.40-1.00 (m, 9H) ppm; MS (ES) 536.27
(M+H); [0777]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-((4-methy-
lpiperazin-1-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine,
compound #9, .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.27 (s,
2H), 7.37 (d, 2H), 7.12 (d, 2H), 3.50 (s, 2H), 2.85 (m, 6H), 2.66
(m, 6H), 2.50 (s, 3H), 1.76 (m, 2H), 1.64 (m, 2H), 1.34 (m, 4H)
ppm; MS (ES) 448.22 (M+H); [0778]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(-
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-di-
amine, compound #10, .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.06 (s,
1H), 8.49 (s, 1H), 7.60 (s, 2H), 7.56 (dd, 1H), 7.17 (d, 1H), 6.93
(t, 1H), 3.15-3.35 (m, 8H), 2.89 (m, 2H), 2.40-2.80 (m, 7H), 1.95
(m, 2H), 1.45-1.75 (m, 8H), 1.37 (m, 4H) ppm; MS (ES) 506.40 (M+H);
[0779]
N.sup.3-(3-fluoro-4-(4-morpholinopiperidin-1-yl)phenyl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #25; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.34 (s, 1H), 7.32
(d, 1H), 7.03 (d, 1H), 6.84 (t, 1H), 3.75 (m, 4H), 3.39 (m, 2H),
2.93 (m, 2H), 2.76 (m, 2H), 2.62 (M, 6H), 2.36 (m, 1H), 1.72-1.95
(m, 8H), 1.43 (m, 4H) ppm; MS (ES) 522.24 (M+H); [0780]
1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-N.sup.3-(4-(4-methyl-
piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #11;
.sup.1H NMR (CDCl.sub.3, 300 MHz) 10.75 (s, 1H), 8.36 (s, 1H), 7.64
(s, 1H), 7.53 (d, 2H), 6.88 (d, 2H), 3.32 (m, 4H), 3.11 (m, 6H),
2.82 (m, 2H), 2.64 (s, 3H), 1.87 (m, 2H), 1.78 (m, 2H), 1.41 (m,
4H) ppm; MS (ES) 434.22 (M+H); [0781]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(2-methyl-1,-
2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #12; .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.26 (s,
1H), 8.21 (s, 1H), 7.34 (dd, 1H), 7.16 (d, 1H), 6.97 (d, 1H), 4.07
(s, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.86 (m, 2H), 2.71 (s, 3H),
2.68 (M, 2H), 1.76 (m, 2H), 1.64 (m, 2H), 1.34 (m, 4H) ppm; MS (ES)
405.21 (M+H); [0782]
N.sup.3-(4-(4-(4-fluorophenyl)piperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexa-
hydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #13; .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.22 (s,
1H), 7.30 (d, 2H), 6.85 (m, 6H), 3.90 (m, 4H), 3.13 (m, 4H), 2.81
(m, 2H), 2.65 (m, 2H), 1.76 (m, 2H), 1.61 (m, 2H), 1.31 (m, 4H)
ppm; MS (ES) 514.18 (M+H); [0783] ethyl
4-(4-(5-amino-1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2-
,4-triazol-3-ylamino)-2-fluorophenyl)piperazine-1-carboxylate,
compound #14; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.36 (s, 1H), 7.40
(dd, 1H), 7.02 (dd, 1H), 6.87 (t, 1H), 6.70 (br s, 2H), 6.52 (s,
1H), 4.16 (q, 2H), 3.64 (m, 4H), 2.97 (m, 6H), 2.78 (m, 2H), 1.87
(m, 2H), 1.70 (m, 2H), 1.44 (m, 4H), 1.29 (t, 3H) ppm; MS (ES)
510.21 (M+H); [0784]
1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-N.sup.3-(4-(2-methyl-
-2-(pyrrolidin-1-yl)propoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine,
compound #15; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.51 (s, 1H), 8.36
(s, 1H), 7.40 (d, 2H), 7.01 (br s, 2H), 6.82 (d, 2H), 4.03 (s, 2H),
3.39 (m, 4H), 2.95 (m, 2H), 2.76 (m, 2H), 1.99 (m, 4H), 1.85 (m,
2H), 1.71 (m, 2H), 1.49 (s, 6H), 1.43 (m, 4H) ppm; MS (ES) 477.19
(M+H); [0785]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #17; .sup.1H-NMR (CDCl.sub.3, 300 MHz) 8.47 (s, 1H), 7.66
(d, 1H), 7.18 (t, 2H), 6.85 (m, 1H), 3.44 (m, 1H), 3.27 (m, 4H),
3.15 (m, 2H), 2.83 (m, 2H), 2.69 (m, 4H), 2.05 (m, 8H), 1.75-1.90
(m, 4H), 1.42 (m, 4H) ppm; MS (ES) 506.30 (M+H); [0786]
1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-N.sup.3-(4-(2-(pyrro-
lidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound
#18; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.46 (s, 1H), 7.41 (d, 2H),
6.85 (d, 2H), 4.30 (m, 2H), 3.38 (m, 2H), 3.26 (m, 4H), 3.13 (m,
2H), 2.86 (m, 2H), 2.03 (m, 4H), 1.86 (m, 4H), 1.42 (m, 4H) ppm; MS
(ES) 449.24 (M+H); [0787]
N.sup.3-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-1-(5-
,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-dia-
mine, compound #19; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.36 (s, 1H),
7.39 (dd, 1H), 7.05 (d, 1H), 6.89 (t, 1H), 6.71 (br s, 2H), 6.59
(s, 1H), 3.40 (m, 4H), 3.11 (m, 4H), 2.97 (m, 2H), 2.83 (s, 3H),
2.78 (m, 2H), 1.87 (m, 2H), 1.62 (m, 2H), 1.44 (m, 4H) ppm; MS (ES)
516.19 (M+H); and [0788]
1-(5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-yl)-N.sup.3-(4-(2-(pyrroli-
din-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound
#22; .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz) 8.38 (s, 1H),
7.46 (d, 2H), 6.84 (d, 2H), 4.26 (m, 2H), 3.46 (m, 2H), 3.56 (m,
4H), 2.89 (m, 2H), 2.73 (m, 2H), 2.05 (m, 4H), 1.75 (m, 2H), 1.67
(m, 2H), 1.36 (m, 4H) ppm; MS (ES) 448.13 (M+H); [0789]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(3-cyclopentyl-1-
,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #26; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.51 (s, 1H),
8.27 (s, 1H), 7.93 (br s, 2H), 7.50 (m, 2H), 7.10 (m, 1H), 2.76 (m,
5H), 2.37 (s, 3H), 2.27 (m, 2H), 1.97-1.21 (m, 12H) ppm; MS (ES)
510.5 (M+H); [0790]
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydro-benzo[d]azocin-8-yl)-1-(6,7--
dimethoxyquinazolin-4-yl)-1H-[1,2,4]triazole-3,5-diamine, compound
#27; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.30 (s, 1H), 9.08 (s,
1H), 8.78 (s, 1H), 8.14 (br s, 2H), 7.75 (m, 1H), 7.36 (s, 1H).
7.11 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 2.70 (m, 5H), 2.25 (m,
2H), 1.97-1.21 (m, 12H) ppm; MS (ES) 515.3 (M+H); [0791]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(2,3,4,5-tetrahy-
drobenzo[b][1,4]dioxocin-8-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #28; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.32 (s, 1H),
8.25 (s, 1H), 7.91 (s, 2H), 7.34 (s, 1H), 7.25 (d, 1H), 6.91 (d,
1H), 4.31 (t, 2H), 4.11 (t, 2H), 2.37 (s, 3H), 1.82-1.75 (m, 4H),
ppm; MS (ES) 444.31 (M+H); [0792]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(9-(pyrrolidin-1-
-yl)-5,6,7,8,9,10-hexahydrobenzo[8]annulen-2-yl)-1H-1,2,4-triazole-3,5-dia-
mine, compound #29; .sup.1H NMR (CDCl.sub.3/MeOD.sub.4, 300 MHz)
7.75 (s, 1H), 7.53 (m, 1H), 7.31 (s, 1H), 7.07 (d, 1H), 3.30 (m,
9H), 3.14 (m, 2H), 2.65-2.90 (m, 2H), 2.42 (s, 3H), 2.01 (m, 4H),
1.81 (m, 2H), 1.75 (m, 1H), 1.55 (M, 1H), 1.10 (m, 1H) ppm; MS (ES)
509.15 (M+H); [0793]
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-9-yl)-1-(5-(tr-
ifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, compound
#30; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.01 (s, 1H), 8.73 (m,
1H), 8.30 (m, 1H), 7.76 (m, 3H), 7.44 (m, 1H), 7.23 (s, 1H), 6.93
(m, 1H), 2.89 (m, 1H), 2.66 (m, 6H), 1.69-1.18 (m, 12H) ppm; MS
(ES) 472.2 (M+H); [0794]
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-(6-flu-
oroquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine, compound #31;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.61 (m, 1H), 9.27 (m, 1H),
8.93 (m, 1H), 8.37 (br s, 2H), 7.99 (m, 2H), 7.57 (m, 1H), 7.17 (m,
1H), 6.97 (m, 1H), 2.91 (m, 1H), 2.71 (m, 6H), 1.69-1.22 (m, 12H)
ppm; MS (ES) 473.2 (M+H); [0795]
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahy-
drobenzo[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine, compound
#32; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 10.2 (s, 1H), 7.88 (m,
2H), 7.80 (m, 1H), 7.52 (m, 3H), 7.31 (m, 3H), 3.69 (m, 1H), 3.07
(m, 2H), 2.87 (m, 2H), 1.96 (m, 6H), 1.68-1.45 (m, 8H) ppm; MS (ES)
460.2 (M+H); [0796]
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenz-
o[d]azocin-9-yl)-1H-1,2,4-triazole-3,5-diamine, compound #33;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.41 (m, 1H), 8.02 (m, 1H),
7.82 (m, 3H), 7.51 (m, 2H), 7.35 (m, 2H), 7.08 (m, 1H), 3.20 (m,
2H), 3.00 (m, 1H), 2.80 (m, 2H), 2.02-1.42 (m, 14H) ppm; MS (ES)
460.1 (M+H); [0797]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-oxo-5,6,8,9,1-
0-pentahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #34; [0798]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7,8-
,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #35; .sup.1H-NMR (DMSO-d6, 300 MHz) 9.08 (br. s, 1H), 8.72
(s, 1H), 7.56 (br. s, 2H), 7.46 (d, J=15.0 Hz, 1H), 7.11 (d, J=8.4
Hz, 1H), 6.91 (t, J=9.0 Hz, 1H), 3.20-3.16 (m, 2H), 3.00-2.96 (m,
2H), 2.63-2.55 (m, 4H), 2.44-2.40 (m, 4H), 2.10-2.00 (m, 1H),
1.90-1.88 (m, 4H), 1.71-1.67 (m, 6H), 1.54-1.37 (m, 6H) ppm; MS
(ES) 506.32 (M+H); [0799]
N.sup.3-(3-fluoro-4-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)-1-(5,6,7,8,-
9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #36; .sup.1H-NMR (DMSO-d6, 300 MHz) 8.92 (br. s, 1H), 8.71
(s, 1H), 7.56 (br. s, 2H), 7.41 (d, J=13.2 Hz, 1H), 7.06 (d, J=8.7
Hz, 1H), 6.45 (t, J=10.2 Hz, 1H), 3.88 (t, J=7.2 Hz, 2H), 3.59 (t,
J=6.3 Hz, 2H), 2.98-2.96 (m, 2H), 2.56 (m, 1H), 2.42 (m, 6H), 1.89
(m, 2H), 1.74-1.68 (m, 6H), 1.42-1.36 (m, 4H) ppm; MS (ES) 478.20
(M+H); [0800]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrrolidin-1-
-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-
-diamine, compound #37; [0801]
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azoci-
n-8-yl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-
-3,5-diamine, compound #38; .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
9.53 (m, 1H), 8.27 (m, 1H), 7.95 (br s, 2H), 7.66 (m, 1H), 7.49 (m,
1H), 7.18 (m, 1H), 3.04 (m, 1H), 2.81 (m, 4H), 2.37 (s, 3H), 2.14
(m, 3H), 1.68-1.22 (m, 13H) ppm; MS (ES) 535.2 (M+H); [0802]
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azoci-
n-8-yl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #39; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.34 (s, 1H),
9.06 (s, 1H), 8.81 (s, 1H), 8.16 (br s, 2H), 7.78 (m, 1H), 7.36 (s,
1H), 7.15 (m, 1H), 7.05 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.48
(m, 1H), 3.02 (m, 4H), 2.06 (m, 5H), 1.84-1.22 (m, 11H) ppm; MS
(ES) 541.2 (M+H); [0803]
1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrrolidin-1-yl)-5,6,-
7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #40; [0804]
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-(7-met-
hylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #41; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.42 (m, 1H),
8.88 (m, 1H), 8.18 (m, 1H), 8.11 (brs, 2H), 7.65 (m, 1H), 7.50 (m,
1H), 7.19 (m, 1H), 3.02 (m, 2H), 2.89 (m, 4H), 2.42 (s, 3H), 1.97
(m, 5H), 1.56 (m, 8H) ppm; MS (ES) 475.2 (M+H); [0805]
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azoci-
n-8-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diam-
ine, compound #42; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.42 (m,
1H), 8.88 (m, 1H), 8.18 (m, 1H), 8.11 (br s, 2H), 7.75 (m, 1H),
7.50 (m, 1H), 7.14 (m, 1H), 3.53 (m, 1H), 3.03 (m, 4H), 2.42 (s,
3H), 2.11 (m, 5H), 1.77 (m, 2H), 1.56-1.22 (m, 9H) ppm; MS (ES)
501.2 (M+H); [0806]
N.sup.3-(7-(cyclohexylamino)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-3--
yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #43; [0807]
N.sup.3-(7-(4-methylpiperazin-1-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyr-
idin-3-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-d-
iamine, compound #44; [0808]
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(4-pheny-
l-5,6,7,8,9,10-hexahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-d-
iamine, compound #45;
.sup.1H-NMR (DMSO-d.sub.6, 300 MHz) 9.60 (broad s, 1H), 9.06 (s,
1H), 7.43-7.50 (m, 3H), 7.41 (m, 1H), 7.33 (m, 2H), 7.21 (m, 2H),
6.93 (t, 1H), 3.53 (m, 2H), 3.26 (m, 2H), 2.99-3.20 (m, 4H),
2.45-2.66 (m, 6H), 2.00-2.10 (m, 3H), 1.64-1.85 (m, 6H), 1.39 (m,
6H); MS (ES) 581.30 (M+H); [0809]
N.sup.3-(4-(4-methylpiperazin-1-yl)phenyl)-1-(4-phenyl-5,6,7,8,9,1-
0-Hexahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #46; .sup.1H-NMR (DMSO-d6, 300 MHz) 8.67 (s, 1H), 7.61 (m,
1H), 7.44 (m, 2H), 7.31-7.40 (m, 4H), 7.20 (s, 1H), 6.79 (d, 2H),
2.97 (m, 6H), 2.65 (m, 2H), 2.40 (m, 4H), 2.18 (s, 3H), 1.76 (m,
2H), 1.35 (m, 6H); MS (ES) 509.31 (M+H); [0810]
N.sup.3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(4-phenyl-5,6,7,8,9,10-he-
xahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #47; .sup.1H-NMR (CDCl.sub.3/MeOD-4, 300 MHz) 7.36-7.45
(m, 4H), 7.30 (m, 1H), 7.26 (m, 2H), 7.16 (m, 1H), 6.90 (t, 1H),
4.28 (m, 2H), 3.79 (m, 2H), 3.47-3.60 (m, 4H), 2.97 (m, 2H), 2.68
(m, 2H), 2.05 (m, 4H), 1.80 (m, 2H), 1.30-1.45 (m, 6H); MS (ES)
542.31 (M+H); [0811]
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(2-chloro-7-me-
thylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #48; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.54 (m, 2H),
8.16 (s, 1H), 7.94 (s br, 2H), 7.62 (d, 1H), 7.36 (s, 1H), 7.23 (d,
1H), 2.67 (s, 3H), 2.48 (m. 2H), 2.35 (m, 2H), 2.15 (m, 2H), 1.87
(m, 2H) ppm; MS (ES) 455.10 (M+H); [0812]
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(7-methylthien-
o[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine, compound
#49; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.51 (m, 2H), 8.14 (s,
1H), 7.90 (s br, 2H), 7.62 (m, 2H), 7.35 (s, 1H), 7.21 (d, 1H),
2.51 (s, 3H), 2.46 (m. 2H), 2.48-2.32 (m, 2H), 2.12 (m, 2H), 1.81
(m, 2H) ppm; MS (ES) 421.15 (M+H); [0813]
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(6,7-dimethoxy-
quinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine, compound #50;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.46 (s, 1H), 9.39 (s, 1H),
9.00 (s, 1H), 8.81 (s, 1H), 8.13 (s, 2H), 7.53 (d, 1H), 7.37 (s,
1H), 7.25 (s, 1H), 7.14 (m, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 2.77
(m, 2H), 2.38 (m, 2H), 2.01 (m, 2H), 1.83 (m, 2H) ppm; MS (ES)
461.13 (M+H), 459.30 (M-H); [0814]
N.sup.3-(6-(4-(azepan-1-yl)piperidin-1-yl)pyridin-3-yl)-1-(5,6,7,8,9,10-h-
exahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine,
compound #51; .sup.1H NMR (CD.sub.3OD, 300 MHz) 8.83 (m, 1H), 8.38
(m, 1H), 8.08 (m, 1H), 7.45 (m, 1H), 4.33 (m, 2H), 3.46 (m, 6H),
3.29 (m, 6H), 3.10 (2H), 2.29 (m, 2H), 1.96 (m, 8H), 1.75 (m, 4H),
1.57 (m, 2H), 1.43 (m, 2H), 1.32 (m, 1H); MS (ES) 517.40 (M+H); and
[0815]
N.sup.3-(6-(4-((pyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-1-(5,-
6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diam-
ine, compound #52.
Testing of the Compounds of the Invention
[0816] The compounds of the invention were tested in the following
assay for their ability to inhibit Axl activity.
Phospho-Akt in-Cell Western Assay
Reagents and Buffers:
[0817] Cell culture plate: 96 well assay plate (Corning 3610),
white, clear bottom, tissue-culture treated. [0818] Cells: Hela
cells. [0819] Starvation medium: For Axl stimulation: 0.5% FCS
(fetal calf serum) in DMEM, plus Axl/Fc (extracellular domain of
AXL fused to immunoglobulin Fc region) (R&D, 154-AL) 500 ng/mL.
[0820] For EGF (epidermal growth factor) stimulation: 0.5% FCS in
DMEM (Dulbecco's modified Eagles medium). [0821] Poly-L-Lysine
0.01% solution (the working solution): 10 .mu.g/ml, dilute In PBS
(phosphate buffered saline). [0822] Axl antibody cross-linking:
[0823] 1.sup.st: Mouse anti-Axl (R&D, MAB154). [0824] 2.sup.nd:
Biotin-SP-conjugated AffiniPure goat anti-mouse IgG (H+L) (Jackson
ImmunoResearch #115-065-003). [0825] Fixing buffer: 4% formaldehyde
in PBS. [0826] Wash buffer: 0.1% TritonX-100 in PBS. [0827]
Quenching buffer: 3% H.sub.2O.sub.2, 0.1% Azide in wash buffer,
Azide and hydrogen peroxide (H.sub.2O.sub.2) are added fresh.
[0828] Blocking buffer: 5% BSA in TBST (tris buffered saline plus
0.1% Tween 20). [0829] Primary antibody: Rabbit anti-human
Phospho-Akt antibody (Cell Signaling 9271): 1.times.250 diluted in
blocking buffer. [0830] Secondary antibody: HRP (horse radish
peroxidase)-conjugated Goat anti-Rabbit secondary, stock solution:
Jackson ImmunoResearch (Goat anti-Rabbit HRP, #111-035-144) 1:1
diluted in glycerol, store at -20.degree. C. The working solution:
1.times.2000 dilution of stock in blocking buffer. [0831]
Chemiluminescent working solution (Pierce, 37030): SuperSignal
ELISA (enzyme linked immunosorbant assay) Pico Chemiluminescent
substrate. [0832] Crystal Violet solution: Stock: 2.5% Crystal
violet in methanol, filtered and kept at ambient temperature. The
working solution: dilute the stock 1:20 with PBS immediately before
use. [0833] 10% SDS: working solution: 5% SDS (sodium
dodecylsulfate), diluted in PBS
Methods:
Day 1:
[0834] A 96 well TC (tissue culture treated) plate was coated with
10 .mu.g/mL poly-L-Lysine at 37.degree. C. for 30 min, washed twice
with PBS, and air-dried for 5 minutes before cells were added. Hela
cells were seeded at 10,000 cells/well and the cells were starved
in 100 .mu.L starvation medium containing Axl/Fc for 24 hrs.
Day 2:
[0835] The cells were pre-treated with test compounds by adding 100
.mu.L of 2.times. test compound to the starvation medium on the
cells. The cells were incubated at 37.degree. C. for 1 hr before
stimulation.
[0836] The cells were stimulated by Axl-antibody cross-linking as
follows: A 5.times. 1.sup.st/2.sup.nd Axl antibody mixture was made
(37.5 .mu.g/mL 1.sup.st/100 .mu.g/mL 2.sup.nd) in starvation medium
and nutated at 4.degree. C. with thorough mixing for 1-2 hours for
clustering. The resulting mix was warmed to 37.degree. C. 50 .mu.L
of 5.times. Axl 1.sup.st/2.sup.nd of antibody cluster was added to
the cells and the cells were incubated at 37.degree. C. for 5
min.
[0837] After 5 minutes stimulation, the plate was flicked to remove
medium and the plate was tapped onto paper towels. Formaldehyde
(4.0% in PBS, 100 .mu.L) was added to fix the cells and the cells
were incubated at ambient temperature for 20 min without
shaking.
[0838] The cells were washed with a plate washer buffer to remove
the formaldehyde solution. The plate was flicked to removed excess
wash buffer and tapped onto paper towels. Quenching buffer (100
.mu.L) was added to each well and the cells were incubated at
ambient temperature for 20 minutes without shaking.
[0839] The cells were washed with a plate washer buffer to remove
the quenching buffer. Blocking buffer (100 .mu.L) was added and the
cells were incubated at ambient temperature for at least an hour
with gentle shaking.
[0840] The cells were washed with a plate washer buffer and diluted
primary antibody (50 .mu.L) was added to each well (blocking buffer
was added to the negative control wells instead). The plates were
incubated overnight at 4.degree. C. with gentle shaking.
Day 3:
[0841] The wash buffer was removed, diluted secondary antibody (100
.mu.L) was added, and the cells were incubated at ambient
temperature for 1 hour with gentle shaking. During the incubation,
the chemiluminescent reagent was brought to ambient
temperature.
[0842] The secondary antibody was removed by washing the cells
1.times. with wash buffer, 1.times. with PBS by plate washer. The
PBS was removed from the plate and the chemiluminescent reagent (80
.mu.L: 40 .mu.L A and 40 .mu.L B) was added to each well at ambient
temperature.
[0843] The resulting chemiluminescence was read with a Luminomitor
within 10 minutes to minimize changes in signal intensity. After
reading the chemiluminescence, the cells were washed 1.times. with
wash buffer and 1.times. with PBS by plate washer. The plate was
tapped onto paper towels to remove excess liquid from wells and
air-dried at ambient temperature for 5 minutes.
[0844] Crystal Violet working solution (60 .mu.L) was added to each
well and the cells were incubated at ambient temperature for 30
min. The crystal violet solution was removed, and the wells were
rinsed with PBS, then washed 3.times. with PBS (200 .mu.L) for 5
minutes each.
[0845] 5% SDS solution (70 .mu.L) was added to each well and the
cells were incubated on a shaker for 30 min at ambient
temperature.
[0846] The absorbance was read at 590 nM on a Wallac photospec. The
590 nM readings indicated the relative cell number in each well.
This relative cell number was then used to normalize each
luminescence reading.
[0847] The results of the ability of the compounds of the invention
to inhibit Axl activity, when tested in the above assay, are shown
in the following Table wherein the level of activity (i.e., the
IC.sub.50) for each compound is indicated in the Table. The
compound numbers in the Table referred to the compounds disclosed
herein as being prepared by the methods disclosed herein:
TABLE-US-00001 TABLE 1 (Ia) ##STR00087## Compound Cpd # Name
R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 IC.sub.50 1
1-(5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-N.sup.3-(4-(2-(pyr-
rolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00088## ##STR00089## H H A 2
1-(5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-N.sup.3-(4-(4-meth-
ylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00090## ##STR00091## H H A 3
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,7-
,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamin-
e H ##STR00092## ##STR00093## H H A 4
N.sup.3-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1-(5,6,7,8,9,10--
hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00094## ##STR00095## H H A 5
N.sup.3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydro-
cycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00096## ##STR00097## H H A 6
(R)-N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00098## ##STR00099## H H B 7
(S)-N.sup.3-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00100## ##STR00101## H H B 8
N.sup.3-(3-chloro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10--
hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00102## ##STR00103## H H A 9
1-(5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-N.sup.3-(4-((4-met-
hylpiperazin-1-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00104## ##STR00105## H H B 10
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7-
,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamin-
e H ##STR00106## ##STR00107## H H A 11
1-(5,6,7,8,9,10-hexahydrocycloocta[c]-pyridazin-3-yl)-N.sup.3-(4-(4-met-
hylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00108## ##STR00109## H H A 12
1-(5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-N.sup.3-(2-methyl-
-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00110## ##STR00111## H H D 13
N.sup.3-(4-(4-(4-fluorophenyl)piperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-he-
xahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00112## ##STR00113## H H D 14 ethyl
4-(4-(5-amino-1-(5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-y-
l)-1H-1,2,4-triazol-3-ylamino)-2-fluorophenyl)piperazine-1-carboxylate
H ##STR00114## ##STR00115## H H B 15
1-(5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-N.sup.3-(4-(2-met-
hyl-2-(pyrrolidin-1-yl)propoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00116## ##STR00117## H H A 16
N.sup.3-(4-(4-Cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydr-
ocycloocta[c]-pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00118## ##STR00119## H HH A 17
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7-
,8,9,10-hexahydrocycloocta[c]-pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamin-
e H ##STR00120## ##STR00121## H H A 18
1-(5,6,7,8,9,10-hexahydrocycloocta[c]-pyridazin-3-yl)-N.sup.3-(4-(2-(py-
rrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00122## ##STR00123## H H A 19
N.sup.3-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00124## ##STR00125## H H B 20
1-(5,6,7,8,9,10-Hexahydrocycloocta[d]-pyrimidin-4-yl)-N.sup.3-(4-(2-(py-
rrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00126## ##STR00127## H H A 21
-(5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidin-4-yl)-N.sup.3-(4-(4-meth-
ylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00128## ##STR00129## H H A 22
1-(5,6,7,8,9,10-hexahydrocycloocta[b]-pyridin-2-yl)-N.sup.3-(4-(2-(pyrr-
olidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00130## ##STR00131## H H A 23
1-(5,6,7,8,9,10-Hexahydrocycloocta[b]-pyridin-2-yl)-N.sup.3-(4-(4-methy-
lpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine H
##STR00132## ##STR00133## H H A 24
N.sup.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6,-
7,8,9,10-hexahydrocycloocta[d]-pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diami-
ne H ##STR00134## ##STR00135## H H A 25
N.sup.3-(3-fluoro-4-(4-morpholinopiperidin-1-yl)phenyl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]-pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00136## ##STR00137## H H B 26
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(3-cyclopentyl-
-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00138## ##STR00139## H H A 27
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydro-benzo[d]azocin-8-yl)-1-(6,-
7-dimethoxy-quinazolin-4-yl)-1H-[1,2,4]triazole-3,5-diamine H
##STR00140## ##STR00141## H H A 28
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(2,3,4,5-tetra-
hydrobenzo[b][1,4]dioxocin-8-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00142## ##STR00143## H H A 29
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(9-pyrrolidin--
1-yl)-5,6,7,8,9,10-hexahydrobenzo[8]annulen-2-yl)-1H-1,2,4-triazole-3,5-di-
amine H ##STR00144## ##STR00145## H H A 30
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-9-yl)-1-(5-(-
trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00146## ##STR00147## H H A 31
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-(6-f-
luoroquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine H ##STR00148##
##STR00149## H H A 32
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobe-
nzo[d]azocin-8-yl)-1H-1,2,4-triazole-3,5-diamine H ##STR00150##
##STR00151## H H A 33
1-(benzo[d]thiazol-2-yl)-N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobe-
nzo[d]azocin-9-yl)-1H-1,2,4-triazole-3,5-diamine H ##STR00152##
##STR00153## H H A 34
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-oxo-5,6,8,9-
,10-pentahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00154## ##STR00155## H H A 35
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(5,6,7-
,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00156## ##STR00157## H H A 36
N.sup.3-(3-fluoro-4-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)-1-(5,6,7,-
8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00158## ##STR00159## H H A 37
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrrolidin-
-1-yl)-(5,6,7,8,9,10-hexahydrocycloocta[d]pyridin-3-yl)-1H-1,2,4-triazole--
3,5-diamine H ##STR00160## ##STR00161## H H A 38
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azo-
cin-8-yl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazo-
le-3,5-diamine H ##STR00162## ##STR00163## H H A 39
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azo-
cin-8-yl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00164## ##STR00165## H H A 40
1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(7-(pyrrolidin-1-yl)-5,-
6,7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamin-
e H ##STR00166## ##STR00167## H H A 41
N.sup.3-(3-cyclopentyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1-(7-m-
ethylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00168## ##STR00169## H H A 42
N.sup.3-(3-(bicyclo[2.2.1]heptan-2-yl)-1,2,3,4,5,6-hexahydrobenzo[d]azo-
cin-8-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-di-
amine H ##STR00170## ##STR00171## H H A 43
N.sup.3-(7-(cyclohexylamino)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin--
3-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamin-
e H ##STR00172## ##STR00173## H H A 44
N.sup.3-(7-(4-methylpiperazin-1-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]p-
yridin-3-yl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-
-diamine H ##STR00174## ##STR00175## H H A 45
N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1-(4-phe-
nyl-5,6,7,8,9,10-hexahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-
-diamine H ##STR00176## ##STR00177## H H B 46
N.sup.3-(4-(4-methylpiperazin-1-yl)phenyl)-1-(4-phenyl-5,6,7,8,9,10-Hex-
ahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00178## ##STR00179## H H B 47
N.sup.3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(4-phenyl-5,6,7,8,9,10--
hexahydrocycloocta[b]-pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00180## ##STR00181## H H B 48
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[d]azocin-9-yl)-1-(2-chloro-7--
methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00182## ##STR00183## H H A 49
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(7-methylthi-
eno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine H
##STR00184## ##STR00185## H H B 50
N.sup.3-(1-oxo-1,2,3,4,5,6-hexahydrobenzo[c]azocin-9-yl)-1-(6,7-dimetho-
xyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine H ##STR00186##
##STR00187## H H A 51
N.sup.3-(6-(4-(azepan-1-yl)piperidin-1-yl)pyridin-3-yl)-1-(5,6,7,8,9,10-
-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine
H ##STR00188## ##STR00189## H H A 52
N.sup.3-(6-(4-((pyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-1-(-
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-di-
amine H ##STR00190## ##STR00191## H H A IC.sub.50 activity: A =
<1 .mu.M B = 1 to 10 .mu.M C = >10 to 20 .mu.M D = >20
.mu.M
[0848] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification and/or listed in the Application Data Sheet are
incorporated herein by reference, in their entireties.
[0849] Although the foregoing invention has been described in some
detail to facilitate understanding, it will be apparent that
certain changes and modifications may be practiced within the scope
of the appended claims. Accordingly, the described embodiments are
to be considered as illustrative and not restrictive, and the
invention is not to be limited to the details given herein, but may
be modified within the scope and equivalents of the appended
claims.
* * * * *